House of Lords - Science and Technology

Select Committee on Science and Technology Sixth Report

CHAPTER 2: The Nature of Allergy

2.1.Since the late 1950s the incidence of allergy in developed countries has risen steadily. In the United Kingdom the incidence of common allergic diseases has trebled in the last twenty years, to become one of the highest in the world.[4] Recent estimates suggest about a third of the population will develop symptoms due to allergy at some point in their lives.[5] No comparable increases in prevalence have been observed in developing countries, but although many hypotheses have been proposed, the true reason for the "allergy epidemic" in the westernised world has yet to be found.

2.2.The pattern of allergic diseases in the United Kingdom, as in many other developed countries, has also changed over the last 50 years. An increasing number of people suffer from food allergy, allergic rhinitis and atopic eczema, and new allergies have emerged such as oral allergy syndrome and latex allergy. The involvement of multiple organs is now seen more frequently and certain allergic conditions appear to be more severe or potentially life-threatening. As an example, peanut allergy is now increasingly common in young children.[6]

2.3.During the course of our inquiry it has become clear that the term "allergy" is used in different ways by doctors and lay people. Our aim in this chapter therefore is to define what allergy means, to distinguish it from intolerance, and to examine the basic mechanisms involved.

Allergy

2.4.The term "allergy" was first coined by Clemens von Pirquet in 1906 to describe an altered or changed reactivity of the immune system to foreign proteins,[7] irrespective of whether this resulted in immunity or a harmful effect. However, today most clinicians restrict the use of the term to situations where an exaggerated sensitivity (hypersensitivity) results from a heightened or altered reactivity of the immune system in response to external substances. These foreign substances that provoke allergies are called allergens and enter the body either by inhalation, swallowing, injection, or contact with the skin, eye or airways. The Royal College of Physicians reported that common allergens include "grass, weed and tree pollens, substances present in house dust … [particularly the faeces of housedust mites], fungal spores, animal products, certain foods, and various chemical agents found in the home and at work."[8]

2.5.Allergy is not a disease but a mechanism which may play a role in a number of disorders.

ALLERGIC MECHANISMS: ATOPIC (IGE-MEDIATED) ALLERGY

2.6.Atopic allergic conditions arise when individuals produce increased amounts of the allergic antibody immunoglobulin E (IgE), a type of antibody which binds particularly strongly to specific receptors on mast cells (specialised cells found in connective tissue and airways). When the cell-associated IgE comes into contact with the specific allergen against which it is directed, the molecules of IgE become "cross-linked" by that allergen, and the mast cell becomes activated. This results in the release of inflammatory chemicals such as histamine and leukotrienes (see Figure 1). Acute symptoms of allergy such as sneezing, spasm of the airways, itching, rash and tissue swelling are caused by histamine, and when there is a large release into the circulation, as in anaphylaxis, histamine causes a fall in blood pressure. Leukotrienes have a more prolonged course of action, causing airway narrowing and swelling which leads to shortness of breath and wheeze.[9]

2.7.The symptoms of chronic allergic disorders, such as a continuous blocked nose or on-going wheeziness, may result from another molecular pathway involving immune cells known as T helper 2 (Th2) cells. This pathway involves the release of cytokines and chemokines, small messenger proteins which recruit other cells into the reaction.[10]

2.8.The majority of people who suffer from IgE-mediated allergy are said to be "atopic". The European Academy of Allergology and Clinical Immunology (EAACI) defines atopy as "a personal or familial tendency to produce IgE antibodies in response to low doses of allergens, usually proteins, and, as a consequence, to develop typical symptoms such as asthma, rhinoconjunctivitis or the atopic eczema/dermatitis syndrome (AEDS)."[11] This means that atopic individuals are more likely to develop these allergic conditions than non-atopic individuals. However, not all atopic individuals do so.

2.9.Atopy is associated with disorders such as hayfever, allergic asthma and eczema. The disorders discussed in this report are mainly atopic in nature, so when the term allergy is used in an unqualified way, it refers to atopic allergy.

ALLERGIC MECHANISMS: NON-ATOPIC (NON-IGE-MEDIATED) ALLERGY

2.10.However, allergy is not as simple as this brief summary seems to suggest. Some conditions are not dependent on IgE but still involve an abnormal immune response to a wide variety of external environmental agents. These conditions are known as non-atopic (non-IgE-mediated). The mechanisms of non-atopic disease are less clearly understood but some disorders (i.e. contact dermatitis) may involve a different subset of immune cells known as T helper 1 (Th1)[12] (see Figure1).

FIGURE 1 Schematic representation of the main mechanisms of allergies and their diseases

The range of allergic disorders

2.11.Allergy plays a role in various disorders and allergic reactions can be acute, chronic, mild or severe. For conditions such as asthma, rhinitis, eczema and urticaria, commonly regarded as allergic in origin, allergy plays a role in some patients but not in others. As an example, asthma may be triggered by allergy, but can also be caused by viral infections, pollution and stress. Skin disorders such as dermatitis, urticaria and angioedema, can be caused by both atopic and non-atopic allergic mechanisms as well as non-allergic pathways. Thus, although swelling, itching and redness are found in many of these conditions it is often very difficult to establish a clear association between a specific allergy and the skin disease. The Royal College of Physicians' report noted that the importance of allergy may also change with time. For example, milk and egg allergy are prevalent in young children but these are often replaced by other allergies as the individual ages.[13] Throughout this report the term "allergic disease" is used as a generic term to refer to disorders in which allergy can play a role. The most common allergic disorders are described in Table 1.

2.12.Although many patients exhibit hypersensitive reactions to food, only some of these cases are caused by true IgE-mediated food allergy, such as an allergy to peanuts. In other cases there may not be any evidence to suggest that their problem is associated with an alteration in the immune system, so their condition is known as a "food intolerance". Examples of these are patients who are unable to digest lactose (due to a constitutional deficiency of the enzyme lactase), patients suffering from food-induced migraine and those who suffer from irritable bowel syndrome (a gut disorder of unknown cause). Various other conditions may be attributable to external agents but do not involve allergic sensitisation, such as alcohol intolerance (caused by a deficiency of the aldehyde dehydrogenase enzyme) and reactions to sulphites, nitrites and food additives.[14]

2.13.Other disorders, such as chronic fatigue syndrome and multiple chemical sensitivity (see para 8.26), may be attributed to allergy even though there is a lack of evidence to suggest they have an allergic basis. The Royal College of Physicians' report commented that these disorders can have a significant impact upon the lives of patients and their families, so it is important to investigate these conditions fully in order to carefully diagnose and manage the underlying disorder.[15]

TABLE 1

Categories of disease related to allergy[16]

Disorder	Symptoms	Common allergens or other causes	Main disease mechanism	Other key features
Allergic rhinitis:	Blocked, runny nose, sneezing, itching and streaming eyes		IgE-mediated	Mild winters and warmer springs mean that pollination in the United Kingdom now starts earlier than it did 50 years ago. Therefore symptoms can be well established by the first week in May and peak around mid-June to early July. When pollen counts are very high, some wheeziness can also coexist with rhinitis, in a condition known as seasonal allergic asthma
Seasonal allergic rhinitis (hayfever or rhinoconjunctivitis)	Worst symptoms occur at the height of summer when vast clouds of grass pollens become airborne	Pollen (commonly grass, but also tree and weed pollen)
Perennial allergic rhinitis	Chronic symptoms occur all year round	Housedust mite, allergens derived from cats, dogs, horses and pet rodents. In some patients, perennial rhinitis is due to non-allergic causes such as infection or structural abnormalities of the airway. A small minority of patients also have underlying immunodeficiency problems
Asthma	Characterised by episodes of wheezy breathlessness, but may also present as an isolated cough, particularly in children. "Non-atopic" asthma often starts later in life and can be more severe	The cause is still uncertain, and it is often difficult to determine the role of allergy. Allergy to housedust mite, pollen, moulds and pets can trigger an attack in a significant proportion of patients; food allergens and additives may rarely trigger symptoms. A significant proportion of patients are not sensitised to allergens so are "non-atopic" or "intrinsic" asthmatics	IgE-mediated	Pathology involves inflammation and muscular contraction of the large and small airways (bronchi and bronchioles—see Figure 2). The consequence is an irritable, easily constricted airway in which a variety of non-specific irritants causes airflow obstruction (bronchial hyper-responsiveness). Triggers include viral infection, exercise, certain drugs, and exposure to fumes or tobacco smoke
Anaphylaxis:	Anaphylaxis describes a group of symptoms affecting several parts of the body, caused by a hypersensitivity reaction to an allergen in a previously sensitised individual. "Anaphylactic shock" is an extreme hypersensitive reaction characterised by an overwhelming sense of impending doom, a dramatic fall in blood pressure, swelling in the throat and mouth, chest tightness, breathlessness from severe asthma and unconsciousness. In a small number of cases, anaphylactic shock results in death		IgE-mediated	A rash may herald that a more severe reaction will occur in the future, but in some cases anaphylactic shock occurs without any previous warning

Sensitivity to insect venom	Some reactions are life-threatening but most result in a temporary irritation or swelling around the site of the sting	Can be caused by wasp or bee stings
Sensitivity to drugs	Rash anywhere in the body	Almost any drug, but the most common causes are penicillin and other betalactam antibiotics		Only a small proportion of adverse drug reactions have an allergic background, and an even smaller proportion are IgE-mediated
Sensitivity to foods	Rash anywhere in the body, especially around the mouth and throat	Peanuts, tree nuts (such as almonds, hazelnuts, walnuts and brazil nuts), milk, eggs, fish and shellfish
Oral allergy syndrome	Swelling in the lips, mouth, tongue or throat	Occurs in tree, grass, weed and latex allergy sufferers immediately after contact with certain foods. A significant proportion of people who are allergic to birch trees, suffer oral allergy syndrome after eating raw apples	IgE-mediated	The reaction is caused by a cross-reaction between the allergen to which the patient is sensitised, and the food protein
Urticaria and Angioedema:	Itching and swollen, red welts known as "hives" or "wheals" on the surface of the skin (urticaria) or deeper in the skin, particularly around the mouth and eyes (angioedema)
Acute	Rash suddenly occurs and usually disappears within 24-48 hours	Food allergy, especially to peanuts, tree nuts or shellfish. Viral infection is more commonly the cause than food allergy	IgE-mediated
Chronic	Symptoms last intermittently or continuously for more than three months, but often clear up without treatment	Underlying cause is rarely found	Non-IgE-mediated
Atopic dermatitis (Atopic eczema)	Chronic, recurrent inflammation of the skin, characterised by intense itching which particularly affects the flexures (creases of skin) at joints such as the wrists, elbows, ankles and knees	Egg or cow's milk allergy sometimes triggers symptoms in children, but this is rarely the case in adults. A number of external influences may trigger or exacerbate symptoms, including emotional stress, irritation of the skin by wool or nylon, infections and vaccinations	IgE-mediated	Patients often also suffer from other atopic disorders such as allergic rhinitis, asthma or both. It is currently thought that atopic dermatitis usually develops first and this then predisposes an individual to the production of IgE and the development of other atopic disorders
Contact dermatitis	Redness, scaling and itching at sites of exposure to the irritant. Can lead to thickening of the skin (lichenification)	Most commonly due to an irritation caused by external substances, but may also result from non-atopic allergic sensitisation to substances in the workplace, or nickel, lanolin and cosmetics	Non-IgE-mediated
Extrinsic allergic alveolitis (EAA): e.g.	Shortness of breath, with or without cough, and in the acute phase there are usually muscular aches, fever and a lack of energy	Repeated or prolonged exposure to agents found in bacteria, animal products and chemicals	Non-IgE-mediated	EAA describes a group of lung disorders caused by an inflammation of the alveoli (air sacs in the lung)
Farmers' Lung		Bacteria found in straw, mouldy hay or grain
Bird Fanciers' Lung		Bird droppings and feathers
Animal Handlers' Lung		Dried urine, hair or animal dander
Coeliac disease	Diarrhoea, failure to thrive (in infants and children), weight loss (in adults) and fatigue	Caused by an allergy to gliadin, a protein found in wheat, barley and rye	Non-IgE-mediated	Occurs in genetically predisposed individuals at all ages after infancy. It is an allergic disorder although the basic mechanism is autoimmune. Management requires a lifelong gluten-free diet

FIGURE 2

Why asthma makes it hard to breathe

BOX 1

The genetics of allergy and asthma

The development of allergic disease depends on interactions between a variety of environmental factors and a susceptibility to developing an allergy. In recent years, several genes have been described which suggest that events at the lining of the airways, or outermost layer of the skin, may be important in the development of asthma or atopic dermatitis.

Several potentially important genes have been shown to influence asthma susceptibility, but their precise role remains unclear. Atopic dermatitis has also been shown to be linked to several chromosome areas.[17] However, despite these discoveries it is doubtful whether genetic modification will play a role in the management of allergy in the foreseeable future.

The progression of allergic disorders

2.14.The "allergic march" describes the progression, or natural history, of allergic disorders in atopic individuals. In general no allergy symptoms are detectable at birth although specific IgE antibody responses to food proteins such as egg and milk may be observed during the first months of life, even in completely breastfed infants. Atopic dermatitis is usually the first manifestation of allergy in infants, but many children with eczema or food allergy in infancy develop rhinitis or asthma in the pre-teen years, which persist into early adulthood, and can last several years or decades.[18]

2.15.However, Professor John Warner, Professor of Paediatrics at Imperial College London, pointed out that having eczema per se does not necessarily lead to the development of other conditions such as asthma, but it is more likely that common underlying factors "predispose you to both conditions" (Q 92). Dr Warren Hyer, a consultant paediatrician at Northwick Park and St Mark's Hospital, told us that "people progress through different manifestations of the allergic march at different rates" (Q 656), but the mechanisms of the allergic march were still unclear, and some individuals might experience spontaneous remission with age.

2.16.The prognosis for each patient is mostly determined by the severity of the condition and the presence of atopic sensitisation. During our visit to Odense University Hospital in Denmark, Dr Arne Høst, Head of the Department of Paediatrics told us that children who suffered from non-IgE-mediated allergic reactions to cow's milk tended to have a good prognosis whilst children with IgE-mediated cow's milk allergy had a higher risk of the allergy persisting, and a higher risk of developing other food allergies, inhalant allergies or asthma and rhinoconjunctivitis.[19]

2.17.Asthmatic wheezing is also seen in early infancy, usually only transiently, but can continue throughout school age and adolescence. Although childhood asthmatics seem to outgrow their disorder in adolescence, partly due to an increasing lung capacity with growth, Professor Warner noted that "the majority, if you do sophisticated lung function tests, still show an abnormality," and many have "a recurrence of symptoms" by the age of 30 (QQ 95-96). This was because, as Professor Peter Burney, Professor of Respiratory Epidemiology and Public Health at Imperial College London told us, people "do not generally lose their allergies" with age (Q94).

2.18.As development of allergy depends on both genetic and environmental factors, the risk of a baby developing atopic symptoms within the first two years of life is strongly related to allergic disease in its parents and siblings. But nutrition, exposure to environmental agents and lifestyle are also important which, as discussed in Chapter 4, may explain why the prevalence of allergy in many developing countries is far lower than that seen in the Westernised world.

4 op cit. Royal College of Physicians, Allergy: the unmet need, 2003, p ix. Back

5 op cit. DH A review of services for allergy, p 31. Back

6 op cit. DH A review of services for allergy, p 27. Back

7 Kay, Clinical and Experimental Allergy 36, 2006, "100 years of 'Allergy': can von Pirquet's word be rescued?," pp 555-559. Back

8 op cit. Royal College of Physicians, Allergy: the unmet need, 2003, p 3. Back

9 op cit. Royal College of Physicians, Allergy: the unmet need, 2003, p 3. Back

10 op cit. Royal College of Physicians, Allergy: the unmet need, 2003, p 4. Back

11 See http://www.eaaci.org/allergydefinitions/english.htm. Back

12 Lebrec et al., Cell Biology and Toxicology 15, 1999, "Mechanisms of drug-induced allergic contact dermatitis," pp 57-62. Back

13 op cit. Royal College of Physicians, Allergy: the unmet need, 2003, p 5. Back

14 ibid. Back

15 ibid. Back