Allergy is an inflammatory disorder of hyperreactivity of the immune system against common environmental exposures. The prevalence of allergy is increasing, both in industrialized and developing nations; the reason for this is unknown. A higher prevalence of allergy is observed in developed nations, as compared with less affluent countries, and migrants to high allergy areas develop allergies in a time-sensitive manner. Access to care is a serious issue with allergy and asthma, leading to higher mortality in places where diagnosis, prevention, and treatment are not readily available.
Allergy develops from a combination of genetic factors and environmental exposures, and is also known as atopy, a genetic predisposition toward overreactive immune responses to harmless environmental exposures. Atopy typically includes the atopic triad: asthma, eczema, and allergic rhinitis. Allergies can affect many organ systems, including airways, gastrointestinal tract, eyes, nose, and skin, and can manifest as asthma, food allergy, allergic rhinitis (hay fever), eczema (atopic dermatitis), or hives (urticaria).
Normally, the immune system protects the body from invading pathogens by recognizing the microbe and generating protective cells and molecules against it. An allergic reaction is also an immune response, but to nonpathogens. Common allergens include house dust mites; cockroaches; cat and dog dander; plant pollens from trees, grasses, and shrubs; foods such as peanuts, shellfish, and eggs; and medications, such as penicillin. Rural and urban areas contain different allergens. For example, air pollution in cities that are heavily industrialized is known to exacerbate asthma, while chicken feathers, dust, and grass pollen have been identified as common triggers in rural areas.
An allergic reaction is classified as a type I hypersensitivity reaction, characterized by secretion of immunoglobulin E (IgE) antibodies. In an allergic reaction, a person must be previously sensitized to the particular allergen, so that the immune system is able to identify and memorize a specific molecular “footprint” for each allergen. On encountering the allergen for the first time, IgE is produced. These IgE antibodies attach themselves to mast cells, which line the organs of the body, or basophils, which are present in blood. Mast cells and basophils contain granules full of inflammatory molecules, including histamine, leukotrienes, and prostaglandins.
Other immune cells also play an important role in allergy and the allergic reaction. Activated B cells (or plasma cells) produce the IgE antibodies selectively in allergic individuals. B cells are also able to make other antibodies (including IgG) against allergens that do not lead to mast cell degranulation but are protective against allergic inflammation. Allergen-specific IgG antibody, but not IgE, has been found in nonallergic individuals, demonstrating that their immune systems can also recognize and respond to the allergen, but without inducing an inflammatory response.
When a previously sensitized person comes in contact with the same allergen for the second time, the allergen crosslinks two or more molecules of IgE on the same mast cell or basophil, leading to degranulation. The release of granules causes the effects of inflammation, either systemically or locally at the site of exposure (lungs, skin, etc.). These can include redness, swelling, itchiness, increased vascular permeability, mucus secretion, and anaphylaxis.
T cells are also important in the pathogenesis of an allergic reaction. The immune deviation hypothesis states that allergies can be explained by the balance between type 1 and type 2 T cell activity. Type 2 helper (Th2) T cells produce molecules that prepare, assist, and exaggerate the IgE inflammatory response. The natural function of Th2 cells is to respond to parasites and extracellular bacteria, while Th1 cells respond to viral and intracellular infections. In several models, deviation toward a Th1 response, away from a Th2 response, can prevent development of an allergic reaction. However, Th1 cells can also synergize with Th2 cells to aggravate allergies, so it is not entirely clear that the Th1/Th2 dichotomy or immune deviation fully explains pathogenesis.
It has also been shown that nonallergic people have regulatory mechanisms in place to thwart a runaway immune response, while allergic individuals have lower levels of these regulatory cells and molecules. A different type of T cell, which is anti-inflammatory and plays a protective role against allergies, is called a regulatory T cell (Treg). Tregs secrete anti-inflammatory cytokines, which counteract the effects of the proinflammatory molecules. The best-supported hypothesis for the pathogenesis of allergy is that it is due to an insufficient development of allergen-specific Tregs expressing anti-inflammatory molecules. All people develop the same reactions to harmless allergens, but only allergic people are missing the anti-inflammatory brigade that prevents allergic reactions.
Atopic disease, especially childhood asthma, has increased in prevalence worldwide since 1980. This increase is most obvious in countries that are rapidly industrializing or becoming westernized. Epidemiologic data and evidence from the immune-deviation hypothesis have given rise to the hygiene hypothesis. Because children get fewer infections in a cleaner, more industrialized age, it has been suggested that Th2 cells are improperly trained in their ability to distinguish harmless and harmful molecules. This results in a hyperresponsiveness of the immune system.
The evidence for the hygiene hypothesis mostly consists of epidemiological studies that suggest associations and correlations, rather than causation. Data for specific microorganisms are limited, but three that have a protective effect against asthma and atopic dermatitis are hepatitis A virus, salmonella, and helminths/parasites. In addition, studies have shown that enrollment in daycare, having several siblings, growing up on a farm, and exposure to bacterial by-products are all negatively correlated with the development of a positive allergy skin test. However, exposure to pigs in early childhood is correlated with an increase in asthma, and cat ownership increases the risk of developing one of the three atopic diseases.
Allergic rhinitis is inflammation of the eyes, nose, and throat upon exposure to an allergen. Mucus secretion, itchy, watery eyes, and frequent sneezing are the hallmarks of allergic rhinitis, also known as hay fever. Skin-prick testing is the gold standard for diagnosis, proving effective in over 80 percent of allergic rhinitis patients tested. Small amounts of common allergens are scratched onto the skin. If the patient is allergic, a red, itchy wheal will appear on the skin within 30 minutes, which can be detected as evidence of a specific allergy. Levels of IgE in the blood are often used as a diagnostic tool in clinics, but a recent study has shown that IgE titer varies between individuals, so that a single blood serum IgE level is not indicative of allergenicity of an individual. In areas without primary care clinics, allergic rhinitis can be diagnosed by noting seasonal variations and the common exposures that trigger a reaction.
Treatments for allergic rhinitis include antihistamines, intranasal steroids to suppress inflammation, and air filters, which have shown mild benefit in reducing indoor allergens. In addition, immunotherapy, involving subcutaneous administration of increasing doses of allergen over a three-to-five-year period, has been shown to cure individuals of their allergies. The mechanism is thought to induce production of protective IgG antibodies as well as expansion of protective anti-inflammatory Tregs that are specific to each allergen. Where immunotherapy is not available, identification and avoidance of the triggering allergen(s) is important.
Asthma is a chronic respiratory disease characterized by attacks of difficulty breathing. Around 300 million people in the world have asthma, and an estimated 400 million will have it by 2025. Not all asthma is related to allergy, but allergies are a common trigger for asthma attacks, as are infections, exercise, cold weather, and environmental exposure to respiratory irritants.
Asthma is diagnosed by a lung function test that measures the volume and force of air entering and leaving the lungs. Leukotriene receptor antagonists have shown effectiveness in asthmatics with allergic rhinitis, and leukotriene receptor antagonists and antihistamines are more effective when used together than either alone. Where treatment and management options are limited for asthma, it can be life threatening. Triggers such as allergens and air pollution should be avoided if possible.
Atopic dermatitis is a chronic inflammatory skin disease that usually begins in early infancy. The rash itself is extremely itchy and is usually located on the inside surface of elbows and knees, as well as the cheeks of infants and hands and feet of older children and adults. The disease only develops where the skin is scratched, earning this disease the name the itch that scratches. Eczema is the fastest growing of all atopic diseases. A high percentage of patients with eczema have positive skin tests to dietary and environmental allergens, and associated atopic disease (asthma, allergic rhinitis) often develops in children with eczema. The prevalence of food allergy in this population is significantly higher than in the general population. Treatments for eczema include topical corticosteroids, oral steroids, T cell immunosuppressant topical creams, and avoidance of allergy-inducing foods.
Anaphylaxis is a systemic reaction to an allergen that can lead to hives, constriction of airways, and even death. Common triggers for anaphylaxis are insect stings from the Hymenoptera family (bees, wasps), penicillin and vancomycin allergy, and food allergy, such as tree nuts or shellfish. Portable epinephrine is the best immediate treatment for an onset of anaphylaxis, while immunotherapy have been shown to be highly effective in preventing subsequent systemic reactions. In areas where epinephrine (adrenalin) is not available, avoidance of triggers is important but often difficult.
Allergy develops from childhood, and around 50 percent of asthma and allergy are thought to be due to genetic factors. Forty to 50 percent of newborns with two atopic parents develop atopic disease, while 20 to 30 percent with single atopic heredity and 10 percent of newborns with no atopic heredity develop some form of the atopic triad.
Children are sensitized to allergens in the order in which they are exposed: food, indoor allergens, then outdoor allergens. In infancy, the early signs of atopy are generally eczema, gastrointestinal symptoms, and frequent wheezing. In later childhood, allergy generally manifests as bronchial asthma and allergic rhinitis.
When healthcare is intermittent or absent, asthma and allergic anaphylaxis are life-threatening conditions. In addition, epidemiological studies have demonstrated a higher prevalence in atopic diseases that correlates with increasing industrialization of a nation and westernized lifestyle of its population. In a study done on Nigerian and Australian children, it was found that with similar levels of atopy, children living in Australia were at a higher risk for asthma. Also, immigrants to countries with high rates of atopy acquire allergies in a time-dependent manner, according to the age they were when they moved. Vaccination rates, ethnicity, environment, and previous infections do not affect this acquisition of allergic sensitization. However, the International Study of Asthma and Allergies in Childhood (ISAAC) has demonstrated a wide range of worldwide prevalence of asthma, allergic rhinitis, and eczema, not always parallel to a nation’s level of industrialization.
The commonly cited link between high socioeconomic status and atopic disease has not been conclusively proven. In studies from the United Kingdom, it was found that there was a higher prevalence of asthma among children in families of high socioeconomic status. One explanation of this is the hygiene hypothesis, that upper-class families live in cleaner conditions. However, an Australian study showed no statistically significant relationship between asthma incidence and social class, and ISAAC data also have not shown this link. It is possible that previous studies linking atopy to elevated socioeconomic status suffered from reporting bias, from less exposure to clinical medicine and less familiarity with the diagnoses. When polled about severe asthma, as opposed to moderate, children in families with low income had high levels.
Asthma; Asthma in Children; Disease and Poverty; Food Allergy.
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