RISK FACTORS FOR ALLERGIC DISEASE

Sports and Allergies

• Moderate and controlled exercise is beneficial for allergic subjects and should be part of their management.

• Vigorous exercise may trigger or exacerbate several allergy syndromes such as bronchospasm, rhinitis, urticaria-angioedema and anaphylaxis. 

• Allergy diagnosis should be part of the routine medical examination in all professional and amateur athletes, in order to adopt adequate preventative and therapeutic measures for controlling the disease, while avoiding potential symptoms occurring on exercise.

The Potential of Genetics in Allergic Diseases 

• Allergic disorders are heterogeneous and involve important gene-environmental interactions. 

• Human genetics has a role to play in understanding susceptibility for disease onset, phenotypes and subphenotypes, severity, response to treatments and natural history. 

• Although candidate gene association studies have provided some insight into the role of genes in disease susceptibility, most new information is emerging from hypothesis-free approaches such as genome-wide association studies. 

• Many early gene association studies were under-powered and the results have not been confirmed in different populations. 

• Genetic factors that influence the expression of atopy are different from those that influence disease manifestations or its severity in specific organs. 

• Poymorphism of a single gene usually accounts for only a small proportion of the disease phenotype. 

• Epigenetic influences involving multiple mechanisms, including methylation of CpG islands in gene promoters, histone acetylation, phosphorylation and methylation and a large number of micro RNAs, explain a proportion of the gene-environmental interactions and trans-generational effects. 

• The genetic epidemiological observations for specific candidate genes in atopy and allergic disease require careful replication, enhanced by international collaboration and the availability of large, well-characterized casecontrol populations for genotyping. The only way to achieve this is to promote greater cooperation among researchers and create multidisciplinary teams including researchers from academia, industry and clinical practice.

Allergens as Risk Factors for Allergic Diseases

• Sensitization (IgE antibodies) to foreign proteins in the environment is present in up to 40% of the population.

• Such sensitization is strongly associated with exposure for proteins derived from pollens, molds, dust mites and cockroaches. 

• For asthma, rhinitis and atopic eczema there is a strong and consistent association between disease and sensitization. 

• The association between sensitization to grass pollens and symptoms of hay fever occurring during the grass pollen season provides strong evidence for a causal role of grass pollen in the disease.

Environmental Risk Factors: Indoor and Outdoor Pollution 

• Epidemiological studies show that indoor and outdoor pollution affects respiratory health, including an increased prevalence of asthma and allergic diseases. 

• Outdoor pollution is associated with substantial mortality; for example in China, outdoor pollution is associated with more than 300,000 deaths annually. 

• Conservative estimates show that exposure to indoor air pollution may be responsible for almost 2 million deaths per annum in developing countries. 

• Exposure to outdoor/indoor pollutants is associated with new onset of asthma, asthma exacerbations, rhinitis, rhinoconjunctivitis, acute respiratory infections, increase of anti-asthmatic drug use, and hospital admissions for respiratory symptoms. 

• Abatement of the main risk factors for respiratory disease and, in particular, environmental tobacco smoke, indoor biomass fuels and outdoor air pollution, will achieve huge health benefits.

Allergy to Drugs and Biological Agents

• Adverse drug reactions (ADR) may affect up to 1/10 of the world’s population and affect up to 20% of all hospitalized patients. 

• More than 10% of all ADR are unpredictable drug hypersensitivity reactions (DHR). 

• Both under-diagnosis and over-diagnosis are common. 

• The most common DHR involve antibiotics such as penicillins, cephalosporins, and sulfonamides, and aspirin and other non steroidal anti-inflammatory drugs.

• The clinical spectrum of DHR involves various organs, timing and severity. 

• DHR can be severe, even life threatening, and are associated with significant mortality rates. Drugs may be responsible for up to 20% of fatalities due to anaphylaxis. 

• DHR have a significant socio-economic impact on both direct costs (management of reactions and hospitalizations) and indirect costs (missed work/school days; alternative drugs). 

• Diagnostic procedures for DHR should also attempt to identify the underlying mechanisms causing the DHR. 

• Diagnosis is critical for DHR management and prevention. Selection of an alternative drug and desensitization is necessary in some cases

Insect Allergy 

• Hymenoptera venom allergy (HVA) is a common global medical problem and refers to subjects who have a sting-induced large local (LL) or systemic allergic reaction (anaphylaxis). A LL reaction is defined as a reaction larger than 10 cm in diameter which lasts over 24 hours in which the signs and symptoms are confined to tissues contiguous with the sting site. Systemic reactions cause generalized signs and symptoms and include a spectrum of manifestations, ranging from mild to life-threatening. Mild systemic reactions may be limited only to the skin and consist of flushing, urticaria, and angioedema. More severe systemic reactions can involve bronchospasm, laryngeal edema, and hypotension. HVA can cause fatal anaphylaxis. 

• The morbidity rate is underestimated; fatal reactions may not be appropriately recorded, accounting for this underestimation. 

• The incidence of positive specific IgE antibodies to venom is high in the general population, but only a fraction of such individuals develop a systemic reaction. 

• Fatal reactions occur in up to 50% of individuals who have no documented history of a previous systemic reaction. 

• HVA impairs long-term quality of life (QOL) and is the cause of substantial socio-economic problems. 

• A subject’s QOL is negatively affected when appropriate diagnosis and education are not achieved and when venom immunotherapy (VIT) (a series of injections of the venom to which the subject is allergic and which essentially cures their disease) is not utilized. 

• HVA can be effectively treated with VIT and appropriate venom therapies.

• HVA poses a problem in occupational settings, especially in bee keepers and greenhouse workers. 

• HVA has important adverse consequences in terms of employment, earning capacity and leisure and sporting activities. 

• HVA has a substantial adverse financial impact on healthcare costs.

Occupational Allergy 

• Occupational allergic diseases represent an important public health issue due to their high prevalence and their socio-economic burden. 

• Occupational asthma (OA) contributes significantly to the global burden of asthma, since the condition accounts for approximately 15% of asthma amongst adults. 

• Allergic contact dermatitis (ACD) is one of the most common occupational diseases. 

• Occupational allergic diseases remain largely underrecognized by physicians, patients, and occupational health policy makers. 

• Occupational allergic diseases can result in long-term health impairment, especially when the diagnostic and avoidance measures are delayed. 

• Occupational allergic diseases lead to important adverse consequences in terms of healthcare resources, employment, earning capacity and quality of life. 

• Occupational allergic diseases are associated with a substantial adverse financial impact for affected workers, insurance or compensation schemes, health services, and employers. 

• Occupational allergic diseases are, by definition, preventable diseases and their burden should be minimized by appropriate preventative strategies.

White Book on Allergy

Atopic Eczema

•  An increase in the worldwide prevalence of atopic eczema has been observed. 

• Atopic eczema is the most common chronic inflammatory skin disease with a varied clinical spectrum. 

• Atopic eczema is often the first manifestation of the atopic patient and early intervention may offer an opportunity to impede or stop the atopic march. 

• Atopic eczema represents an important public health issue due to its impact on quality of life and its socio-economic burden.

Anaphylaxis 

• Epinephrine, at appropriate doses, is the drug of choice to treat anaphylaxis. 

• There is lack of consensus about the definition of anaphylaxis and this lack of consensus in definition contributes to the variability in its identification, treatment and the use of epinephrine. 

• The variability and severity of anaphylaxis is somewhat dependent on the route by which the allergen or inciting agent is delivered, i.e. parenteral versus oral administration; the former is commonly associated with more severe reactions. 

• There is a variety of other terms which describe anaphylaxis which cause confusion, especially with its definition and treatment. These include: generalized systemic reaction; systemic allergic reaction; constitutional reaction; and serious hypersensitivity reaction. 

• Anaphylaxis includes both allergic and non-allergic etiologies.

• The term “anaphylactoid” is outdated

Food Allergy 

• Globally, 220 – 250 million people may suffer from food allergy. 

• Food allergy significantly affects the quality of life of sufferers (mainly children). 

• Stakeholders must be prepared to meet the needs of patients by enhancing the diagnostic process, the traceability of responsible foods, and the availability of substitute foods, assisting hospitalized patients, and preventing mortality. 

• Large areas in the world lack legislation on food labelling.

• As diagnostic and therapeutic decision strategies are not clear-cut, evidence-based guidelines are necessary for clinicians, patients, governments and industry to deal with the challenge of food allergy. Such guidelines, eg, the WAO recommendation on the Diagnosis and Rationale Against Cow’s Milk Allergy (DRACMA) are available and are ready to be implemented. 

• Epidemiologic studies are necessary, in particular, in less developed areas of the world. 

• Oral desensitization represents a promising approach to reduce the burden of disease caused by food allergy.

Urticaria and Angioedema 

• Urticaria is a heterogeneous group of disease sub-types characterised by wheals (fleeting elevations of the skin lasting approximately 24 hours) and/or angioedema (deeper swellings of skin and mucus membranes). 

• Three major categories exist: a) spontaneous occurrence of wheals, associated with acute and chronic urticaria; b) wheals and angioedema elicited by particular stimuli, and in particular physical urticarias: and c) other urticarial disorders such as exercise-induced urticaria. 

• Urticaria occurs frequently with a lifetime prevalence above 20%.

• Except for acute urticaria, diagnostic and therapeutic procedures can be complex and referral to a specialist is often required.

• Untreated, chronic urticaria has a severe impact on quality of life and impairs productivity by up to 30%.

• The socio-economic impact of urticaria is great, since it is a disease which primarily occurs in people of working age. 

• Moderate to severe urticaria requires specialist treatment. In many health care systems worldwide, access to specialty care is insufficient.

THE BURDEN OF ALLERGIC DISEASE

Allergic Rhinitis 

• Allergic rhinitis (AR) results from an IgE-mediated inflammation of the nasal mucosa. 

• The disease currently affects between 10% and 30 % of the population. 

• Studies indicate that prevalence rates are increasing worldwide. 

• The classification proposed in the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines is useful for the implementation of treatment. 

• AR is a risk factor for asthma. 

• Other co-morbidities of AR include: sinusitis, nasal polyposis, conjunctivitis, otitis media with effusion, upper respiratory infections, breathing through the mouth, and sleep disorders.

• AR has a significant impact on patients based on the degree of the severity of their symptoms. It has psychological effects, interferes with social interactions, and creates an economic burden not only for the affected subject, but for the family and for the society at large. 

• Management is based on patient education, environmental control measures, pharmacotherapy and specific immunotherapy.

Allergic Conjunctivitis 

• Allergic conjunctivitis is an increasingly prevalent allergic disease, with the same clinical gravity as allergic asthma and allergic rhinitis.

• The umbrella term “allergic conjunctivitis” includes distinct clinical entities, from mild but disturbing forms due to IgE sensitization to aeroallergens; to forms of keratoconjunctivitis where the severe allergic inflammation, with corneal involvement, is more difficult to diagnose and treat, and may lead to permanent ocular damage and even loss of vision.

Rhinosinusitis 

• Rhinosinusitis (RS) is one of the most common and expensive medical conditions. 

• RS occurs in a number of forms, the most common of which are either acute or chronic. 

• Initial treatment of RS is usually by a primary care physician (PCP) and if unsuccessful, the PCP should refer either to a surgeon or to an allergist for specialized care. 

• In the vast majority of cases, RS is controlled by proper medical management without the need for surgery. 

• Surgery should only be considered in those patients who are properly managed but in whom a number of medical treatment programs fail. 

• The Allergist, who is trained in allergy, immunology, microbiology, internal medicine and/or pediatrics combined with an expert knowledge of nasal and sinus anatomy and appropriate pharmacology, is best suited to manage RS.

Asthma 

• Asthma is a life-long chronic inflammatory disorder of the airways, associated with variable structural changes, that affects children and adults of all ages. It is associated with airway hyperresponsiveness and airflow obstruction that is often reversible either spontaneously or with treatment. 

• When uncontrolled, asthma can cause death, and can markedly interfere with normal activities, seriously impacting an individual’s quality of life.

• Because of under-diagnosis and inadequate treatment, asthma presents a serious public health problem throughout the world; especially in low and middle income countries.

• Atopy - the genetic predisposition to develop IgEmediated sensitivity to common aeroallergens, is the strongest identifiable predisposing factor to the development of asthma, especially in children.

• There was a sharp increase in the prevalence, morbidity, and mortality associated with asthma beginning in the 1960s and 1970s in the so-called “Westernized” countries of the world. 

• The prevalence of asthma in different countries varies widely, but the disparity is narrowing due to rising prevalence in low and middle income countries as they adopt a more Western-type lifestyle. It is plateauing in high income countries. 

• Inhaled corticosteroids are currently the most effective antiinflammatory medications to treat persistent asthma. 

• The monetary costs of asthma are substantial and include both direct medical costs and the indirect costs, the latter associated with time lost from work and premature deaths. 

• National efforts to tackle asthma as a public health problem, such as the program introduced in Finland, produce remarkable benefits that are reflected in dramatic reductions in deaths and hospital admissions.

• Many barriers exist to a reduction in the worldwide burden of asthma. 

• There are unmet diagnostic, therapeutic, educational and financial needs to achieve better worldwide control of asthma.

 • More effort is needed to focus on ways to improve the management of asthma by focusing on disease control rather than treating acute episodes. This concept has to be embedded in healthcare programs. 

IMMUNOLOGY

Skin Test Wheal and Flare Mechanism: 

• Introduction of antigen into the skin causes local mast cell activation via cross-linking of preformed, antigen-specific, membrane-bound IgE.

• The release of preformed histamine from mast cells causes increased vascular permeability via smooth muscle contraction and development of wheal; inflammatory mediators initiate neural reflex vasodilation, leading to development of flare.

CLINICAL PEARLS 

• Skin testing is a practical, reliable, and well-tolerated method of establishing IgE-mediated disease. • Interpretation of skin testing should be done by an experienced practitioner, in the presence of positive and negative controls, and may be confounded by dermatographism or antihistamine use.

• The presence of a positive skin test documents the presence of allergen-specific IgE antibody. Diagnosis of allergy can be made only by correlating skin testing results with the presence of clinical symptoms.

Allergen immunotherapy: Definition, indication, and reactions

Specific allergen immunotherapy is the administration of increasing amounts of specific allergens to which the patient has type I immediate hypersensitivity. It is a disease modifying therapy, indicated for the treatment of allergic rhinitis, allergic asthma, and hymenoptera hypersensitivity. Specific IgE antibodies for appropriate allergens for immunotherapy must be documented. Indications for allergen immunotherapy include (1) inadequate symptom control despite pharmacotherapy and avoidance measures, (2) a desire to reduce the morbidity from allergic rhinitis and/or asthma or reduce the risk of anaphylaxis from a future insect sting, (3) when the patient experiences undesirable side effects from pharmacotherapy, and (4) when avoidance is not possible. Furthermore, patients may seek to benefit from economic savings of allergen immunotherapy compared with pharmacotherapy over time. Several studies have reported that immunotherapy in children with allergic rhinitis appears to prevent the development of new allergic sensitizations and/or new-onset asthma. Humoral, cellular, and tissue level changes occur with allergen immunotherapy including large increases in antiallergen IgG4 antibodies, a decrease in the postseasonal rise of antiallergen IgE antibodies, reduced numbers of nasal mucosal mast cells and eosinophils, induction of Treg cells, and suppression of Th2 more than Th1 lymphocytes. There is a corresponding increase in IL-10 and transforming growth factor beta. In the United States, allergen immunotherapy is administered by the subcutaneous route in the physician’s office, whereas primarily in some countries in Europe, it is administered for allergic rhinitis and asthma by the sublingual route by the patient at home.

Specific allergen immunotherapy, often called “allergy shots,” has been defined as the administration of increasing amounts of specific allergens to which the patient has type I immediate hypersensitivity. The purpose of allergen immunotherapy is to provide protection against the allergic symptoms and inflammatory reactions associated with natural exposure to these allergens. Although the single best marker that explains immunotherapy’s efficacy is unknown, there are many immunologic changes that occur with immunotherapy

INDICATION AND DURATION

 Immunotherapy is indicated for patients who have clinically significant IgE-mediated allergic rhinitis,asthma,4 and hymenoptera sensitivity.5 Specific IgE for appropriate allergens must be documented and symptoms should correlate with exposure to those specific allergens selected for immunotherapy.6–8 Other indications for allergen immunotherapy include inadequate symptom control despite pharmacotherapy and avoidance measures, undesirable side effects from pharmacotherapy, and when avoidance is not possible.In addition, immunotherapy may prevent the development of new sensitizations and/or new-onset asthma. The relative contraindications to allergen immunotherapy include severe or uncontrolled asthma, significant cardiovascular disease, and
-blocker use.Immunotherapy is not currently approved for food allergy or chronic urticaria and/or angioedema. However, the most recent immunotherapy practice parameter suggests an expanded indication, atopic dermatitis in subjects with aeroallergen sensitization. Multiple controlled studies have shown that immunotherapy is effective treatment for allergic rhinitis due grass, ragweed, and birch pollen.Immunotherapy with house-dust mite vaccines is an effective treatment for both allergic asthma and allergic rhinitis. Studies favoring allergen immunotherapy in patients with asthma have been published for grasses, trees (birch),ragweed, cat, and fungi (Alternaria and Cladosporium).Patients with mild asthma are more likely to benefit from immunotherapy than patients with moderate or severe asthma who may be at increased risk for adverse reactions to immunotherapy. To appropriately choose allergens for cutaneous testing and immunotherapy, it is important to be familiar with the significant aeroallergens in a patient’s geographic location

Immunologic changes with immunotherapy

Antibody changes 

Increase in allergen-specific IgG (specifically IgG4) 

Early increase and late decrease in serum-specific IgE 

Decrease in seasonal rise of specific IgE 

Cellular changes 

Decreased mediator release from mast cells, 

basophils, and eosinophils 

Reduction of tissue mast cells and eosinophils 

Induction of regulatory T cells and suppression of Th2 Th1 cells 

Increased secretion of IL-10 and TGF-
 

Decrease in histamine-releasing factors 

Skin testing in allergy

Skin tests are used in addition to a directed history and physical exam to exclude or confirm IgE-mediated diseases such as allergic rhinitis, asthma, and anaphylaxis to aeroallergens, foods, insect venoms, and certain drugs. There are two types of skin testing used in clinical practice. These include percutaneous testing (prick or puncture) and intracutaneous testing (intradermal). Prick testing involves introducing a needle into the upper layers of the skin through a drop of allergen extract and gently lifting the epidermis up. Other devices are available for prick testing. Intracutaneous (intradermal) testing involves injecting a small amount of allergen (0.01–0.02 mL) into the dermis. The release of preformed histamine from mast cells causes increased vascular permeability via smooth muscle contraction and development of a wheal; inflammatory mediators initiate a neural reflex causing vasodilatation, leading to erythema (the flare). Prick testing methods are the initial technique for detecting the presence of IgE. They may correlate better with clinical sensitivity and are more specific but less sensitive than intradermal testing. Sites of skin testing include the back and the volar aspect of the arm. Although the back is more reactive, the difference is minimal. By skin testing on the arm, the patient can witness the emergence and often sense the pruritus of the skin test reaction. Because more patients are sensitized (have IgE antibodies and positive skin test reactions) than have current symptoms, the diagnosis of allergy can be made only by correlating skin testing results with the presence of clinical symptoms.

Skin tests are used in addition to a directed history and physical exam to exclude or confirm IgEmediated diseases1 such as allergic rhinitis,2 asthma,3 and anaphylaxis4 to aeroallergens,5 foods,6 insect venoms,7 and certain drugs.8 Skin testing attempts to detect the presence of allergen-specific IgE bound to mast cells by eliciting mast cell degranulation to the specific allergen being tested. This may help confirm the suspicion that a patient’s symptoms are related to immediate hypersensitivity to this allergen. Currently, two types of skin testing are used in clinical practice. These include percutaneous testing (prick or puncture) and intracutaneous testing (intradermal). Prick testing involves introducing a needle into the upper layers of the skin through a drop of allergen extract and gently lifting the epidermis up. Several other percutaneous skin testing implements are available commercially. Intracutaneous (intradermal) testing involves injecting a small amount of allergen (0.01–0.02 mL) into the dermis.

Prick testing methods are the initial technique for detecting the presence of IgE. They may correlate better with clinical sensitivity and are more specific but less sensitive than intradermal testing.9–11 In addition, intradermal testing carries a slightly higher risk of a systemic reaction (0.05% versus 0.03% for a prick test), although the risk is still low. Because of this risk, testing should begin with prick testing, and then proceed to intradermal testing if prick testing is negative and there remains a high degree of clinical suspicion. In the past 30 years, six fatalities have been attributed to intradermal testing; five of these patients had asthma and a lack of prior prick testing. One fatality from prick testing has ever been identified; this patient received over 90 prick tests to food allergens at one time and had preexisting asthma.12 Intradermal testing has not proven beneficial in the diagnosis of food allergy; therefore, the risk to patients is not justified. A physician should always be available to give emergency treatment if necessary, and patients should be observed for at least 20 minutes after testing

H1-receptor antagonists should be held for a minimum of 24–72 hours before skin testing based on the specific pharmacokinetics of each drug. Other drugs with antihistaminic properties, such as metoclopramide, histamine-2 receptor blockers, and tricyclic antidepressants, may affect test results and should be held before testing if possible.13 Refer to Table 1 for the elimination half-lives (t 1⁄2) of several commonly prescribed medications. Short courses of oral corticosteroids will not affect testing results; however, topical corticosteroids may decrease or inhibit skin reactivity. These should not be applied to the test site for at least 1 week before testing. Patients receiving immunotherapy may have decreased skin reactivity. Leukotriene antagonists do not significantly affect skin test reactivity.
2-Adrenergic agonists, decongestants, theophylline, and cromolyn will not affect skin testing

Sites of skin testing include the back and the volar aspect of the arm. Although the back is more reactive, the significance of this is minimal.10 Use of the arm as the test site has the advantage of being able to place a tourniquet above the site should a systemic reaction occur. Skin chosen for testing should be clear of dermatitisThe skin chosen is cleaned with alcohol. Allergen extracts, positive control (histamine), and negative control (saline or allergen diluent) are placed 2–5 cm apart. One source of skin testing error is placing sites too close together resulting in spread of one allergen extract to another site and inability to accurately record the extent of erythema from two positive sites close together. False negative or positive reactions may occur with insufficient or excessive skin penetration. If prick testing reveals minimal or equivocal reaction to an allergen, one might choose to proceed with intradermal testing with a 100- to 1000-fold dilution of allergen extract.

Standardized extracts should be used to facilitate comparisons between clinicians. Note that use of standardized doses does not always confer equal potency. One study found that the content of major allergen varied significantly among the 12 standardized extracts tested. Extracts should be refrigerated at 4°C. They should contain glycerin to decrease the loss of potency that occurs with time

Testing should be graded within 15–20 minutes.15 Several different grading systems exist, one of which is shown in Table 2. The mean diameter of the wheal and erythema are recorded with the presence or absence of pseudopodia. Physicians should quantitate the actual size on the data sheet and not solely a grade so that results might be better shared among practitioners. Clinicians also are urged to use a comprehensive data sheet recording the brand of extract, dilutions used, device chosen, mean diameters of wheal and erythema, and specific grading system key. 

Interpretation of skin tests may be more difficult in patients with dermatographism. False positive reactions with dermatographism can be distinguished from true positive reactions that are secondary to IgE because the former fade more quickly. Special attention should be paid to the difference between the sizes of the reactions from allergen extracts compared with the negative control. No significant differences in skin test reactivity have been noted for gender. Infants and the elderly, however, may have decreased skin reactivity and thus smaller wheal size. Additionally, darkly pigmented skin can have larger histamine wheals compared with light skin.

DRUGS

Medicines often are implicated in triggering undesired immunologic reactions. True drug allergy represents 6 –10% of all adverse drug reactions and is overreported by individuals. Most drugs are too small (
1000 Da) to incite allergic sensitization alone. To cause an allergic reaction, a reactive metabolite of the drug must bind to a macromolecular carrier for antigen processing. The drug metabolite in the carrier molecule complex is known as a hapten. This makes skin testing difficult for diagnostic accuracy. Large molecular weight drugs (heterologous antisera, insulin, streptokinase, and l-asparaginase), which are 4000 Da, and medicines that have enough distance between determinants to be bivalent (quaternary ammonium muscle relaxants and aminoglycosides), may provoke an allergic response without forming a hapten–protein complex. 

LATEX 

Natural rubber latex is a product of the rubber tree Hevea brasilensis. Sensitization is present in 75% of patients with spina bifida and 6.5% of the general population. Health care providers and patients with urological problems requiring catherization are also at increased risk. Clinical manifestations of IgE-mediated disease include allergic rhinitis, asthma, contact urticaria, and anaphylaxis. The incidence of IgE-mediated reactions to latex has declined mostly because of the development of powder-free, low-protein gloves. 

INGESTED ALLERGENS 

Food allergy is common and appears to be increasing; it can be divided into class 1 and class 2. Class 1 food allergy is considered “traditional” and occurs in the gastrointestinal tract. Class 2 food allergy is caused by allergic sensitization to inhalant allergens that cross-react with food allergens. Class 1 allergens are 10 –70 kDa and are heat, acid, and protease stable. Common class 1 allergens are cow’s milk, chicken egg, peanut, soybean, fish, and shrimp. Thirty-five percent of children with moderate to severe atopic dermatitis have an associated food allergy,15 and 6% of asthmatic children have associated food allergy. Peanut is the most common food allergy in individuals 4 years old. There has been a dramatic increase in the number of children with peanut allergy with one study noting peanut allergy prevalence of 1.4% in 2008 versus 0.8% in 2002 in the United States. Studies are currently looking at environmental factors that may result in this increased prevalence. 

Cross-reactivity between members of a food allergen group varies. Cross-reactivity between peanuts and other legumes is 5%, between tree nuts 35%, between different fish 50%, and 75% between members of the shellfish family. Cross-reactivity also occurs between aeroallergens and certain food allergy resulting in class 2 food allergies. This is known as pollen–food syndrome (previously oral allergy syndrome) and manifests as pruritus with or without angioedema of the lips, tongue, palate, and posterior oropharynx. Shared allergen sensitivities have been reported between ragweed and the gourd family (watermelon, cantaloupe, zucchini, and cucumbers) and bananas. Birch pollen shares allergen sensitivities with apples, carrots, parsnips, celery, hazelnuts, potatoes, celery, and kiwi. Tree and grass pollen share allergens with apples, tree nuts, peaches, oranges, pears, cherries, fennel, tomatoes, and carrots. Often, cooking or peeling these foods reduces symptoms of pollen–food syndrome.

Reviewing the properties of common allergens reinforces the foundation of controlling clinical allergy symptoms, which is avoidance of allergen exposure. Their properties also form the basis for developing diagnostic and therapeutic opportunities.

IMMUNOLOGY

 • An allergen is typically a protein or glycoprotein that can induce an IgE-mediated immune response with an associated clinical reaction. 

 • Size of pollen determines clinical manifestation of allergy. Particles between 20 and 60
m in diameter can be carried in the wind and cause nasal and ocular symptoms. Particles
7
m can deposit in the airways and cause symptoms of asthma. 

• True drug allergy represents 6 –10% of all adverse drug reactions. Skin testing is difficult because most drug allergens are small metabolites of the implicated drug and they must haptenize a carrier protein to induce an immune response. 

CLINICAL PEARLS

 • Most tree pollens do not have significant cross-reactivity and are released in the spring in the United States. In the upper midwestern United States, tree pollination occurs in mid to late March until May. 

• Grass pollen comes from the Poaceae family, has significant cross-reactivity, and is typically released in the late spring and early summer in the United States. In the upper midwestern United States, this time is from mid-May to the end of July. 

• Weed pollens are released mostly in the autumn in the United States with ragweed being the major allergen from August 15 to October 1 in the upper midwestern United States. 

• Global warming has shifted the floristic zones in North America to higher latitudes. Ragweed has increased in size and pollen production because of increased CO2 and temperature. 

• Fungal spores and mycelial elements are released preferentially in warm, humid environments. The first hard frost of late autumn decreases outdoor mold spores. 

• Dust mites thrive in warm, humid conditions and provide allergen through their fecal particles, enhanced by intrinsic enzymic activity. 

• Cat allergen may last in a home for up to 6 months after the source is removed. It can be isolated from saliva, urine, dander, and from sebaceous glands.

• The most common class I food allergens are cow’s milk, chicken egg, peanut, soybean, fish, and shrimp. There has been an increase in the prevalence of peanut allergy in children. 

• Pollen–food syndrome occurs because of cross-reactivity between aeroallergens and certain food proteins.

FUNGI

Fungi produce airborne spores and mycelial elements that are believed to contribute significantly to allergic disease throughout the world. These allergens are typically 3–30
m in diameter. With few exceptions, such as Alternaria in asthma, Aspergillus in allergic bronchopulmonary aspergillosis, and various fungi in allergic fungal sinusitis, the clinical importance of common fungi has been difficult to assess. Alternaria alternata (major allergen Alt a 1) species are common outdoor molds that have been associated with triggering respiratory arrest in patients with asthma.7 Cladosporium (major allergens Cla h 1, 2) is also a common outdoor mold species, and like Alternaria, it has a seasonal prevalence in the warmer months between spring and autumn. The first hard frost of late autumn decreases spore counts significantly until warm weather returns. In contrast, Aspergillus fumigatus (major allergen Asp f 1) and Penicillium citrinum (Pen c 13,18) species are common indoor molds and may provide allergenic triggers throughout the year. High spore counts in homes are associated with warm, humid environments and may be reduced by air conditioning in the summer, removal of mold in homes with contamination, preventing water damage, and dehumidification if needed.

ENVIRONMENTAL CHANGES 

Climate changes due to global warming are expected to increase temperatures by 1–2°C in this century. This will affect vegetation and will likely result in a higher allergic disease burden. The 2006 U.S. Department of Agriculture hardiness zone map showed a shift northward of floristic zones, which influence the type of native vegetation found in a region.8 This shift exemplifies the effect of global warming on the type of trees and other plants that can survive in a given latitude. In addition, studies have shown increased size and pollen production of ragweed with increased CO2. 9 This was especially seen in urban areas where CO2 levels and temperatures were higher than in rural areas.

DUST MITES 

Dust mites, particularly Dermatophagoides pteronyssinus (major allergen Der p 1) and Dermatophagoides farinae, ingest human epithelial scales and obtain water from the ambient water in the air. They produce feces that provide a perennial allergen source within homes. Dust mites are small (0.33 mm long), eight-legged animals that are present in pillows, mattresses on box springs, sofas, and carpets (shag much more than lownap carpets). They thrive in warm, humid conditions and, therefore, peak in the summer months in the United States. The typical allergen size is 1–10
m in diameter, and its ability to cause allergic respiratory disease is enhanced by intrinsic enzymic activity that penetrates the respiratory mucosal barrier and promotes inflammation

ANIMAL AEROALLERGENS 

Animals produce allergens in forms unique to each species. Dander (desquamated epithelium), saliva, urine, hair, and feathers are the major allergen sources. Cat allergen, most importantly Fel d 1, is found mainly in cat saliva but also in sebaceous glands in the skin and in urine of male cats. Allergen size can be 5
m, allowing cat allergen to reach the small bronchioles, causing symptoms of asthma. It is buoyant and “sticky,” which means it easily remains airborne and may last in a home for up to 6 –9 months after the source is removed. Dog allergen, particularly Can f 1, is present in dander, saliva, urine, and serum. There are allergens specific to dog breeds, but all breeds produce allergenic proteins (even poodles and “hairless” dogs).10 Rodent dander sensitivity occurs in occupational exposure of laboratory workers, but allergenic protein in rodent urine may also contribute to allergic disease in infested homes.

COCKROACH 

Blatella germanica (German cockroach) and Periplaneta americana (American cockroach) are the two most common species of cockroach infesting domestic homes and public buildings. The German cockroach is most prevalent in the United States and has an affinity for warm, humid environments. Increased cockroach infestations have also been noted in the inner cities. Sensitization to cockroach extract, including the best-studied allergens Bla g 1 and Bla g 2, are more common in urban settings.11 Cockroach protein, like dust-mite allergen, becomes airborne when disturbed and falls quickly

HYMENOPTERA 

 In brief, the venoms are introduced parenterally by an insect sting from either vespids (yellow jackets, hornets, and wasps) or apids (honeybees). Vespid allergens are largely cross-reactive, but people sensitive to bee venom usually are not sensitive to vespid venom. Fire ants, located in the southeastern United States, also belong to the Hymenoptera order.

An overview of allergens

An allergen is any antigenic substance that can mediate an immediate hypersensitivity reaction with an associated clinical reaction in an individual. Common allergens include pollens, fungal spores, house-dust mites, and animal epithelial materials but can also include drugs, biological products, and insect venoms. Most allergens are proteins or glycoproteins that range in molecular weight from 5000 to 100,000 Da, although polysaccharides and low molecular weight substances also may be allergenic.1 Little is known, but much research is dedicated to determining the distinguishing facts that make an antigen capable of inducing IgE production (an allergen) in contrast to antigens that induce other immunologic responses (IgG and IgA). Factors that have already been shown to increase immunogenicity of an antigen include molecular size, solubility, stability, conformational fold, and duration of exposure

Allergens enter the body via inhalation, ingestion, or may be injected. Genetic predisposition and environmental factors determine if an individual will be sensitized to an allergen, and then subsequent allergen exposure of sufficient concentration triggers a physiological response by interacting with specific IgE bound to mast cells and basophils. The ensuing inflammatory cascade elicits a variety of signs and symptoms in the allergic spectrum. The allergic response is dependent on the route of exposure. If exposure is to an inhaled aeroallergen, the allergic response will be a respiratory reaction in nature. Ingested or injected exposure gives rise to gastrointestinal, cutaneous, or systemic reactions. 

An allergen is recognized by the International Union of Immunologic Societies as a protein that has allergenicity in at least five individuals.2 Individual allergens are further divided into major and minor allergens when it comes from the same source, e.g., giant ragweed pollen or cat dander. Major allergens result in an IgE response in 50% of allergic individuals allergic to the specific source, whereas minor allergens cause an allergic response in
50%. Although “minor” is in the name, they still cause a significant allergic response in an individual. 

Nomenclature for allergen proteins has been established by the International Union of Immunologic Societies. The standard nomenclature uses the first three letters of the genus, followed by the first letter of the species, and then an Arabic numeral; they are not italicized. 

POLLENS

For pollen to be clinically significant as an aeroallergen, it must be buoyant, present in significant numbers, and be allergenic. Most pollens that cause clinical disease are 20 – 60
m in diameter.2 This small size allows exposure through wind carriage and contact with the respiratory mucosa and conjunctiva. Particles
7
m tend to deposit in the airways, and those
3
m may enter the distal airways. Pollen immunogenicity, plant abundance, proximity to living environments, and regional geography determine specific pollens that are responsible for local allergic sensitization.2 

Grass pollen is the most common cause of allergic rhinitis and asthma worldwide because of the wide distribution of wind-pollinating grasses. Most are 20 –25
m in diameter and, therefore, tend to cause symptoms of rhinitis rather than asthma. Most grasses belong to the same family (Poaceae) and have significant cross-reactivity, with the exceptions of Bermuda and Bahia grass, which are subtropical grasses. Ryegrass (major allergen Lol p 1) and Timothy grass (major allergen Phl p1) are among the most important allergenic grasses. Grass pollen is typically released in the afternoon, and in the Midwest, is prevalent in the months of May through July. Many southern areas, such as Florida and southern California, have grass seasons lasting as long as 10 –11 months. 

Ragweed pollen is the most important cause of allergic rhinitis and pollen asthma in North America. Ambrosia artemisiifolia (short ragweed; major allergen Amb a 1) and Ambrosia trifida (giant ragweed; Amb t 5) are the most important ragweed pollen allergens. Pollen grains are 16 –20
m in diameter and are notorious for triggering allergic symptoms in the central and eastern United States; Ontario, Canada; and increasing locations in Europe.5,6 Weed pollen release depends on seasonal daylight variation and is released typically in the morning during the autumn season in the United States. A single ragweed plant may expel 1 million pollen grains in a single day. It possesses the ability to travel hundreds of miles from its source. In the Chicago area, ragweed pollen is prevalent from August 15 to October 1.