Allergic diseases in the dentist practice.

Allergic diseases in the dentist practice.

Other allergic ( not atopic ) disease.

Emergency conditions in allergy.

 

Allergіc (atopic) diseases

Etiology

Allergy is a distorted (excessive) immune response of the organism to the exogenous agent. Allergy arises as the failure of the normal functioning of the immune system. Antigen is taken as threat to existence of the organism, and it is considered as allergen.

Viennese paediatrician Baron Clemens von Pirquet coined the term "allergy" (from the Greek "allos" meaning changed or altered state and "ergon" meaning reaction or reactivity) in 1906. Von Pirquet used the term to describe an altered reaction he had observed in patients, which he put down to the influence of external factors, an allergen , on the immune system.

Pathogenesis

         Initially (in 1968) Jell and Coombs proposed their classification of the hypersensitivity reactions as the classification of the types of the allergic reactions.

        At present of vital importance in the pathogenesis of allergic reactions is the 1st type and partially the 3rd and 4th types of reactions (chronic hives, urticarias). The 3rd type of reactions can participate in the pathogenesis of bronchial asthma.

         There are three stages of the allergic reactions (as one of the forms of the hypersensitivity reactions): pathoimmune, pathochemical, pathophysiological.

Diagnostics of the allergic diseases

I. Allergic anamnesis. A detailed anamnesis is a basic information source, necessary for diagnostics and treatment of the allergic diseases. While examining patients with the allergic diseases special attention should be paid to:

1. variability of the symptoms (they develop and disappear rapidly, they develop in the specific place or in the specific season)

2. individual allergic anamnesis

3. family allergic anamnesis

II. Physical examination. The organs and the systems, which are most frequently affected with the allergic diseases: the skin, eye, respiratory organs are examined especially attentively.

Basic principles:

1. Not to fail to note the affection of the skin, it is necessary to investigate the entire skin. A patient can not mention about the skin manifestations, considering them insignificant, not related to the disease or feeling shy of them.

IgE-mediated reactions to extrinsic antigens

(Charles A. Janeway et al., Immunobiology, 1999 with change)

 

 

2. While examining the eyes it is possible to reveal hyperemia and edema of the conjunctiva, lacrymation and discharge from the eyes.

3. It is compulsorily to examine the nose, and rhinoscopy is carried out.

4. We may reveal wheezing auscultatively.

III. Laboratory studies. With their aid it is possible only to confirm or deny the diagnosis, based on the data of the anamnesis and physical examination as well as estimate the effectiveness of treatment and follow-up the state of patient.

1. The blood count.

1) An increase in the number of the eosinophils up to 5-15%.

a. Moderate eosinophilia (15-40% of the total number of leukocytes) is encountered not only in the allergic diseases, but also in the malignant neoplasms, for example, in lymphogranulomatosis, immunodeficiencies, congenital defects of the heart, cirrhosis of the liver, nodular periarteritis, herpetiformdermatitis, or during the radiation therapy, application of some medicines and the peritoneal dialysis.

b. Expressed eosinophilia (50-90% of the total number of leukocytes) is usually observed in helminthiases, for example, in the syndrome of larva migrans.

c. The absolute number of the eosinophils can be calculated, after determining the number of leukocytes and leukocyte formula.

2) Absolute and relative lymphocytosis. A substantial change in the relationship of neutrophils/leukocytes.

2. Eosinophils in the smears. In exacerbation of the allergic diseases eosinophils predominate among the cells in the smears of the phlegm, discharge from the nose or eyes, in the concomitant infection there are neutrophils.

3. Total level of IgE in the serum. An increase in the total level of IgE in the serum confirms the diagnosis of the allergic disease, although the normal level of IgE does not exclude it. A radio-immunosorbent test (RAST) and solid-phase (IFA) allows to determine even the low concentrations of IgE (less than 50 IU/ml). It is necessary to know the method of determining the level of IgE and the normal indices, accepted in this laboratory for the evaluation of the results of laboratory investigations. Approximately 70% of adult patients with bronchial asthma and allergic rhinitis have the level of IgE exceeding the normal index by two standard deviations. More than 95% children with a high level of IgE suffer from allergic diseases. The level of IgE may be especially high (more than 1000 IU/ml) in diffuse neurodermatitis and atopic diseases of the respiratory organs.

a. Indications for determining the total level of IgE in the serum.

1) Differential diagnostics of exogenous bronchial asthma and allergic rhinitis, especially in the children of the young age.

2) Differential diagnostics of the atopic diseases of the skin, especially in children.

3) The estimation of the risk of the allergic diseases of the lungs in children with bronchiolitis.

4) Diagnostics and estimation of effectiveness in the treatment of allergic bronchopulmonary aspergillosis.

5) Diagnostics of immunodeficiencies.

6) Diagnostics of medicinal allergy.

7) Diagnostics of myelomatosis.

 In detection of the high level of IgE, first of all, helminthiases are excluded.

4. Determination of the levels of specific IgE in blood serum (IFA diagnostics, ELISA and immunoblotting) to different allergens.

5. Immunogram. The signs of the allergic diseases:

- Absolute and relative lymphocytosis;

- Eosinophilia;

- An increase (more than 2.8) in the index of immunoregulation (Tx/Tc) (CD4/CD8):

- An increase in the absolute and relative quantity of the B-lymphocytes;

- A reduction of the complement content;

- An increase in the levels of the circulating immune complexes;

- An increase in the autoantibodies to the tissues of the organs - targets (the skin, mucous membrane of the nose, bronchi, lungs)

IV. Skin test. There are cutaneous – puncture and scarification and intracutaneous tests. The positive results of skin tests (erythema and blister at the site of the allergen introduction) are of a diagnostic value only in combination with the data of the anamnesis, physical and laboratory investigations.

Indications and selection of the allergens. The basic indication for making the skin tests is development of the allergens, contact with which causes the disease. The diagnostic and therapeutic medicines of allergens are manufactured in the form of the concentrated or diluted extracts. There are diagnostic remedies of the allergens for the cutaneous and intracutaneous tests. The period of usability of the concentrated extracts of allergens is 2-3 years.

Technique of making

1) Patch tests applied. Method is to apply an allergen to a patch which is then placed on the skin. This may be done to pinpoint a trigger of allergic contact dermatitis.

2) Scarification tests. Scarification scratches are made on the skin, on which the drops of the dilute solution of the allergen are placed.

3) The puncture tests (prick-test). Skin-prick testing remain the "gold standard" for identifying clinically relevant allergens. The skin is cleaned by 70% isopropyl or ethyl alcohol. So that the blisters would not merge, the distance between the adjacent punctures must be not less than 2 cm. A drop of the allergen extract is put on each selected point in the dilution 1:10, 1:20 or the undiluted standardized preparation is used, and the skin is pierced.

4) Intracutaneous tests are made in doubtful results of the puncture and scarification tests. The allergen extracts in the dilution of 1: 100 are used for the intracutaneous tests. When less than five puncture or scarification tests are positive, intracutaneous tests can be carried out immediately. If the positive puncture or scarification tests are more, intracutaneous tests are carried out next day. Intracutaneous tests with the food allergens are not made.

Evaluation of the results

1) One and the same method is always used for the evaluation of the results of skin tests, most habitual for the study.

2) Impairment of the technology of skin tests, the use of the allergen preparations with expired date, the tests made against the background of treatment with drugs decreasing skin sensitivity lead to the pseudonegative results. The intake of H₁- blockers is withdrawn for 48 hr, hydroxizine, terfenadine, loratadin and tricyclic antidepressants – for 96 hr and astemizole - 4 weeks prior to the study. Theophylline, adrenostimulators (inhalation and for the internal administration) and cromolin do not influence the skin sensitivity.

3) Introduction of the incorrectly prepared solutions of the allergens (incorrect selection of osmolarity and pH, presence of the irritating substances), impairment of the technology of making skin tests, for example, intracutaneous introduction of more than 0.02 ml of the allergen solution, urticate dermographism, introduction of the substances, which cause the release of histamine (for example, the extracts of food allergens), leads to the pseudopositive results.

4) Results of the skin tests are compulsorily compared with the data of anamnesis, physical and laboratory investigations.

During assessment of the skin tests it is necessary to consider:

1) Skin tests allow to determine rather precisely the cause of allergic rhino-conjunctivitis, but are less informative of exogenous bronchial asthma.

2) While making mass studies, especially in the children of young age, the mixtures of allergens are used. Since during mixing of the allergen solutions their concentration is reduced, the skin tests with the mixtures of allergens are frequently negative. Therefore, if the data of anamnesis and clinical picture indicate allergy, and skin tests with the mixtures of allergens are negative, clean allergens are used for tests.

3) When food allergy is manifested by hives, Quincke's edema or by anaphylactic shock, skin tests with the food allergens are usually positive. However, their diagnostic significance is small, since together with the truly positive skin tests to the food allergens pseudopositive ones are frequently observed. However, negative skin tests have larger diagnostic value, since they indicate the absence of allergy to the specific food allergens with accuracy. If the results of skin tests are positive in food allergy, provocation food tests are made for confirmation of the diagnosis by the double blind method with the use of placebo as the control. If food allergy is accompanied by anaphylactic reactions, these tests are contraindicated.

4) Skin tests are not informative in diffuse neurodermatitis. Of large diagnostic significance in this disease are the provocative tests - inhalation, application and food. Provocation food tests are positive approximately in 30% of children with diffuse neurodermatitis.

5) The value of skin tests is small in the medicinal allergy, since usually the allergy is caused not by the drug itself, but its metabolites, which cannot be determined. Skin tests are made only with the protein allergens, for example, with insulin, sera, and penicillins.

V. Provocation test is a method of development of sensitization, based on the introduction of the allergen in the target organ. There are sublingual, endonasal and inhalation provocation tests.

Allergen-induced bronchoconstriction

 Inhalation of allergens in sensitized subjects develops into bronchorestriction within 10 minutes, reaches a maximum within 30 minutes, and usually resolves itself within one to three hours. In some subjects, the constriction does not return to normal, and recurs after three to four hours, which may last up to a day or more. The first is named the early asthmatic response, and the latter the late asthmatic response.

The major advantage of the provocation tests consists in the larger authenticity of their results.

The main disadvantages in the provocation tests consist in the following:

1) it is possible to make a test only with one allergen during one visit;

2) it is difficult to assess quantitatively the results of the study, especially in allergic rhinitis or conjunctivitis;

3) they yield badly to standardization;

4) they are combined with a high risk of severe allergic reactions, for example, bronchospasm, therefore, only an experienced doctor should make them. Provocation tests are contraindicated, when there are indications of the immediate development of hives, Quincke's edema, bronchospasm or anaphylactic shock in contact with this allergen in anamnesis.

Provocation tests are frequently made in food allergy, since the skin tests are not informative in this case.

VI. Functional diagnostics.

Pulmonary function tests - study of the function of external respiration (spirometry and Peak flow) is used for differential diagnostics of the allergic and nonallergic diseases of the lungs, evaluation of reactivity of the bronchi, severity of these diseases and effectiveness of their treatment. The main tests to measure lung function include:

1) spirometry (this test measures the narrowing of your bronchial tubes by checking how much air you can exhale after a deep breath and how fast you can breathe out)

2) peak flow (a peak flow meter is a simple device that measures how hard you can breathe out)

3) bronchodilator reversibility testing

4) bronchoconstriction testing

 5) nitric oxide test  (this test is sometimes used to diagnose and monitor asthma. It measures the amount of a gas called nitric oxide you have in your breath. If your airways are inflamed — a sign of asthma — you may have higher than normal nitric oxide levels. This test isn't widely available).

Figure VIII.1. Schematic diagram illustrating idealised shapes of flow-volume curves and spirograms for obstructing, restrictive and mixed ventilatory defects (David P. Johns, Rob Pierce, Spirometry, 2008).

 

Interpretation of Ventilatory Function Tests:

1. Normal results is 80–100% of the predicted value.

2. Abnormal values are:

- mild lung dysfunction—60–79%

- moderate lung dysfunction—40–59%

- severe lung dysfunction—below 40%

Peak Expiratory Flow Rate (PEFR)

Peak Expiratory Flow Rate (PEFR) is the greatest flow that can be sustained for 10 milliseconds on forced expiration starting from full inflation of the lungs. It is Methodic:

- stand up or sit up straight

- make sure the indicator is at the bottom of the meter (zero)

- take a deep breath in, filling the lungs completely

- place the mouthpiece in your mouth; lightly bite with your teeth and close your lips on it

- be sure your tongue is away from the mouthpiece

- blast the air out as hard and as fast as possible in a single blow

- remove the meter from your mouth

- record the number that appears on the meter and then repeat steps one through seven two times

Record the highest of the three readings in an asthma diary. This reading is your peak expiratory flow (PEF). To ensure the results of your peak flow meter are comparable, be sure to use your meter the same way each time you take a reading.

Peak Flow Zones (recommend for patients):

The zones will help you check your asthma and take the right actions to keep it controlled. The colors used with each zone come from the traffic light.

Green Zone (80 to 100 percent of your personal best) signals good control. Take your usual daily long-term-control medicines, if you take any. Keep taking these medicines even when you are in yellow or red zones.

Yellow Zone (50 to 79 percent of your personal best) signals caution: your asthma is getting worse. Add quick-relief medicines. You might need to increase other asthma medicines as directed by your doctor.

Red Zone (below 50 percent of your personal best) signals medical alert! Add or increase quick-relief medicines.

Bronchodilator reversibility testing

 This test uses spirometry and a type of drug called a bronchodilator (salbutamol, terbutaline, ipratropium bromide). Bronchodilator reversibility testing may help to differentiate COPD and asthma. There is presently no universal agreement on the definition of significant bronchodilator reversibility. According to the ATS/ERS the criteria for a significant response in adults is: >12% improvement in FEV1 (or FVC) and an absolute improvement of >0.2 L

Bronchoconstriction testing

- dosed exercise testing (a spirometry breathing test is done before and after you exercise on a treadmill) , inhaling cold air,  inhaling saline solution,  inhalations of histamine and methacholine. 

 

The x-ray examination

a. Roentgenography of the chest on primary examination is made in all patients with the allergic diseases of the lungs. The roentgenography of the chest allows to exclude pneumonia, atelectasis and pneumothorax, which can complicate the severe attack of bronchial asthma.

b. Investigation of the paranasal sinuses is made on suspicion of acute or chronic sinusitis - the frequent complication of the allergic diseases of the upper respiratory tract.

Treatment of the allergic diseases

Glucocorticosteroids

         They are the most effective and pathogenetically substantiated drugs for treatment of the allergic diseases. They act at all stages of pathogenesis (pathoimmune, pathochemical, pathophysiological).

         The main effect at the pathophysiological stage in on the epithelium of the blood vessels (they decrease the permeability) and the main symptom with the disease are eliminated (edema, hypersecretion, hyperemia).

         At the pathoimmune stage they block release of cytokines (interleukins and antibodies) by the immunocompetent cells, they contribute to the decrease of the eosinophil number. At the pathochemical stage they contribute to the stabilization of the membranes of mast cells and basophils.

         They are used:

- in acute states - parenterally (prednisolone, hydrocortisone, dexamethasone)

- systematically - orally and intramuscularly prolonged forms - drugs- depot – effect for a month (polcortolon, diprospan)

- locally - inhalation forms, nasal sprays, ointments and creams.

Anti-inflammatory effects of corticosteroid therapy

(Charles A. Janeway et al., Immunobiology, 1999 with change)

 

Antihistamine drugs (blockers of H₁ - histamine receptors)

           They are effective only upon transfer from the pathochemical stage to the pathophysiological one.

Drugs of the first generation:

Dimedrol (Diphenhydramine), Tavegil (Clemastine), Phencarol (Quifenadine), Pipolphen, Diprazin (Promethazine hydrochloride), Diazoline (Mebhydrolin), Suprastin (chloropyramine), (Chloropyramine), Peritol (Cyproheptadine)

Peculiarities of pharmacokinetics and the mechanism of action:

- Competitive (with histamine) blockade of H₁ - receptors – drugs should be taken frequently (3-4 times in a 24 hour period), and in the large doses (risk of the toxic action);

- penetrate through the blood-brain barrier - sedative side-effect (sleepiness) + potentiate the effect of analgesics and antipyretics;

- Irritate the GIT mucosa - the side-effect is diarrhea, therefore the intake is after meal (adsorption velocity from the bowels is lowered);

- In the prolonged intake (more than 10 days) tachyphylaxis develops (addiction) - effectiveness is lowered;

- bind with the blood proteins (risk of the toxic effect during dehydration, cachexia and secretory dysfunction of the kidneys);

- muscarine-like effect (anticholinergic action) - they decrease the secretion of the mucous glands of the respiratory system – they are contraindicated in diseases of the respiration organs in presence of the thick phlegm in the bronchi (they reduce the drainage function of the bronchi).

Drugs of the second generation:

Hismanal, histalong (Astemizol), Claritin (Loratadine), Zirtek (Cetirizine), Cestin (Ebastine), Trexil (terfenadine)

Peculiarities of pharmacokinetics and the mechanism of action:

     They are noncompetitive blockade of H₁ - histaminic receptors; they do not penetrate through the blood-brain barrier; they do not irritate the GIT mucosa; tachyphylaxis does not develop; do not bind with the blood proteins; anticholinergic action is absent.

Drawbacks:

1. Trexil – there are cases of sudden death (it contributes to significant prolongation of P-Q interval) because of the cardiotoxic effect.

2. They are converted into active metabolites in the liver (they suppress the activity of the cytochromes of the hepatocytes).

         Drugs of the third generation (active metabolites of the drugs of the second generation): Telfast (Fexofenadine), Erius (dezloratadine), Aleron (levocetirizine)

         Their drawbacks are still under study.

        According to the last recommendations of allergologists intake of the drugs of the first generation is indicated in the emergency allergic states, since they are in the injection forms, and the administration of the drugs of the second and third generation is indicated for the course therapy.

         At the same time the drugs of the second and third generation do not exceed those of the first generation in the manifestation of the antiallergic effect. Furthermore, many people are noted to have individual sensitivity (selective) to the antihistamine drugs. There may be higher efficacy in intake of the drugs of the first generation and minimum reaction after the intake of the drug of the second or third generation.

Stabilizers of the mast cell membranes

        They are effective at the pathochemical stage and ketotifen - upon transfer from the pathochemical stage to the pathophysiological one (it also possesses antihistaminic effect).

         Cetotifen, sodium cromolin (intal, cromolin, cromogexal, cromoglin etc), Nedocromil of sodium (Tiled).

        They are intended for the prolonged course (the minimum period is 2 months). Cetotifen is for internal administration (the main indication is food allergy - the skin forms of allergy). Cromolin and sodium nedocromil act only locally - in the form of inhalers (cromolin is also in the form of nasal spray and in the form of capsules. Nalcrom is used in the allergic diseases of GIT and food allergy).

Anti-leucotriene drugs (inhibitors of leucotriene metabolism)

        They are effective at the pathoimmune stage and upon transfer from the pathoimmune stage to the pathochemical one. They are zafirlucast, montelucast. The indication is bronchial asthma. They are less effective than inhalation of corticosteroids.

Selectively binds to human immunoglobulin E

Omalizumab is an injectable drug that is used for treating asthma. Omalizumab is a monoclonal antibody targeting the high-affinity receptor binding site on human immunoglobulin IgE. Bound IgE is not available for basophil binding, degranulation is attenuated, and allergic symptoms are reduced. In asthma trials, omalizumab reduced inhaled corticosteroid and rescue medication requirements and improved asthma control and asthma quality of life in moderate to severe allergic asthmatics with disease poorly controlled by inhaled corticosteroids. In trials of patients with poorly controlled moderate to severe seasonal allergic rhinitis, omalizumab reduced the severity of exacerbations and rescue medication use, and improved rhinitis-related quality of life.

Specific immunotherapy

         It is based on the introduction of different dilutions of the causally significant allergen into the organism according to the specific scheme (with a strict observance of dosages and periods of introduction). The mechanism of action:

- the production of the so-called blocking antibodies - IgG (development of sufficient amount of the B-lymphocytes pool in the organism secreted the blocking antibodies instead of specific Ig E and Ig G₄ to the introduction of concrete allergen);

 - the production and release of many of the proinflammatory mediators (particularly cytokines ) are diminished. This may be via a direct effect on mast cells and eosinophils or an immunoregulatory effect mediated by specific populations of lymphocytes;

- after an initial rise, allergen-specific IgE levels in the plasma fall with allergen immunotherapy. This is thought to be due to active immunoregulatory mechanisms that alter how a specific individual responds to a particular allergen.

Not all mechanisms are likely to be active in every treated patient. It is the effective method of treatment of allergic reactions for: dust; pollen; mite; dander and insect venom.

Allergic reactions occur when an individual who has produced IgE antibody in response to an innocuous antigen, or allergen, subsequently encounters the same allergen.

 

 

 

The allergen triggers the activation of IgE-binding mast cells in the exposed tissue, leading to a series of responses that are characteristic of allergy. As we learned, there are circumstances in which IgE is involved in protective immunity, especially in response to parasitic worms, which are prevalent in less developed countries. In the industrialized countries, however, IgE responses to innocuous antigens predominate and allergy is an important cause of disease. Almost half the populations of North

America and Europe have allergies to one or more common environmental antigens and, although rarely lifethreatening, these cause much distress and lost time from school and work. Because of the medical importance of allergy in industrialized societies, much more is known about the pathophysiology of IgE-mediated responses than about the normal physiological role of IgE. The term allergy was originally defined by Clemens Von Pirquet as "an altered capacity of the body to react to a foreign substance," which was an extremely broad definition that included all immunological reactions. Allergy is now defined in a much more restricted manner as "disease following a response by the immune system to an otherwise innocuous antigen." Allergy is one of a class of immune system responses that are termed hypersensitivity reactions. These are harmful immune responses that produce tissue injury and may cause serious disease.

Hypersensitivity reactions were classified into four types by Coombs and Gell. Allergy is often equated with type I hypersensitivity (immediate-type hypersensitivity reactions mediated by IgE), and will be used in this sense here.

In this chapter we will first consider the mechanisms that favor the production of IgE. We then describe the pathophysiological consequences of the interaction between antigen and IgE that is bound by the high-affinity Fc receptor (Fc RI) on mast cells. Finally, we will consider the causes and consequences of other types of immunological hypersensitivity reactions.

IgE-mediated reactions to extrinsic antigens.

All IgE-mediated responses involve mast-cell degranulation, but the symptoms experienced by the patient can be very different depending on whether the allergen is injected, inhaled, or eaten, and depending also on the dose of the allergen.

There are four types of hypersensitivity reaction mediated by immunological mechanisms that cause tissue damage.

Types I-III are antibody-mediated and are distinguished by the different types of antigens recognized and the different classes of antibody involved. Type I responses are mediated by IgE, which induces mastcell activation, whereas types II and III are mediated by IgG, which can engage Fc-receptor and complementmediated effector mechanisms to varying degrees, depending on the subclass of IgG and the nature of the antigen involved. Type II responses are directed against cell-surface or matrix antigens, whereas type III responses are directed against soluble antigens, and the tissue damage involved is caused by responses triggered by immune complexes. Type IV hypersensitivity reactions are T cell-mediated and can be subdivided into three groups. In the first group, tissue damage is caused by the activation of macro-phages by TH1 cells, which results in an inflammatory response. In the second, damage is caused by the activation by TH2 cells of inflammatory responses in which eosinophils predominate; in the third, damage is caused directly by cytotoxic T cells (CTL).

The production of IgE.

 

 

 

IgE is produced by plasma cells located in lymph nodes draining the site of antigen entry or locally, at the sites of allergic reactions, by plasma cells derived from germinal centers developing within the inflamed tissue. IgE differs from other antibody isotypes in being located predominantly in tissues, where it is tightly bound to the mast-cell surface through the high-affinity IgE receptor known as Fc RI. Binding of antigen to IgE cross-links these receptors and this causes the release of chemical mediators from the mast cells, which may lead to the development of a type I hypersensitivity reaction. Basophils and activated eosinophils also express Fc RI; they can therefore display surface-bound IgE and also take part in the production of type I hypersensitivity reactions. The factors that lead to an antibody response dominated by IgE are still being worked out. Here we will describe our current understanding of these processes before turning to the question of how IgE mediates allergic reactions.

Allergens are often delivered transmucosally at low dose, a route that favors IgE production.

 

There are certain antigens and routes of antigen presentation to the immune system that favor the production of IgE. CD4 TH2 cells can switch the antibody isotype from IgM to IgE, or they can cause switching to IgG2 and IgG4 (human) or IgG1 and IgG3 (mouse). Antigens that selectively evoke TH2 cells that drive an IgE response are known as allergens.

Much human allergy is caused by a limited number of inhaled small-protein allergens that reproducibly elicit IgE production in susceptible individuals. We inhale many different proteins that do not induce IgE production; this raises the question of what is unusual about the proteins that are common allergens. Although we do not yet have a complete answer, some general principles have emerged. Most allergens are relatively small, highly soluble proteins that are carried on desiccated particles such as pollen grains or mite feces. On contact with the mucosa of the airways, for example, the soluble allergen elutes from the particle and diffuses into the mucosa.

Allergens are typically presented to the immune system at very low doses. It has been estimated that the maximum exposure of a person to the common pollen allergens in ragweed (Artemisia artemisiifolia) does not exceed 1 μg per year! Yet many people develop irritating and even life-threatening TH2-driven IgE antibody responses to these minute doses of allergen. It is important to note that only some of the people who are exposed to these substances make IgE antibodies against them.

 

Scanning electron micrograph of D. pteronyssimus with some of its fecal pellets.

Genetic factors contribute to the development of IgE-mediated allergy, but environmental factors may also be important.

As many as 40% of people in Western populations show an exaggerated tendency to mount IgE responses to a wide variety of common environmental allergens. This state is called atopy and seems to be influenced by several genetic loci. Atopic individuals have higher total levels of IgE in the circulation and higher levels of eosinophils than their normal counterparts. They are more susceptible to allergic diseases such as hay fever and asthma. Studies of atopic families have identified regions on chromosomes 11q and 5q that appear to be important in determining atopy; candidate genes that could affect IgE responses are present in these regions. The candidate gene on chromosome 11 encodes the β subunit of the high-affinity IgE receptor, whereas on chromosome 5 there is a cluster of tightly linked

genes that includes those for IL-3, IL-4, IL-5, IL-9, IL-12, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF). These cytokines are important in IgE isotype switching, eosinophil survival, and mast-cell proliferation. Of particular note, an inherited genetic variation in the promoter region of the IL-4 gene is associated with raised IgE levels in atopic individuals; the variant promoter will direct increased expression of a reporter gene in experimental systems. Atopy has also been associated with a gain-of-function mutation of the α subunit of the IL-4 receptor, which is associated with increased signaling following ligation of the receptor. It is too early to know how important these different polymorphisms are in the complex genetics of atopy.

A second type of inherited variation in IgE responses is linked to the MHC class II region and affects responses to specific allergens. Many studies have shown that IgE production in response to particular allergens is associated with certain HLA class II alleles, implying that particular MHC:peptide combinations might favor a strong TH2 response.

For example, IgE responses to several ragweed pollen allergens are associated with haplotypes containing the MHC class II allele DRB1*1501. Many individuals are therefore generally predisposed to make TH2 responses and specifically predisposed to respond to some allergens more than others. However, allergies to common drugs such as penicillin show no association with MHC class II or the presence or absence of atopy.

There is evidence that a state of atopy, and the associated susceptibility to asthma, rhinitis, and eczema, can be determined by different genes in different populations. Genetic associations found in one group of patients have frequently not been confirmed in patients of different ethnic origins. There are also likely to be genes that affect only particular aspects of allergic disease. For example, in asthma there is evidence for different genes affecting at least three aspects of the disease phenotype IgE production, the inflammatory response, and clinical responses to particular types of treatment. Some of the best-characterized genetic polymorphisms of candidate genes associated with asthma are shown in, together with possible ways in which the genetic variation may affect the particular type of disease that develops and its response to drugs.

The prevalence of atopic allergy, and of asthma in particular, is increasing in economically advanced regions of the world, an observation that is best explained by environmental factors. The four main candidate environmental factors are changes in exposure to infectious diseases in early childhood, environmental pollution, allergen levels, and dietary changes. Alterations in exposure to microbial pathogens is the most plausible explanation at present for the increase in atopic allergy. Atopy is negatively associated with a history of infection with measles or hepatitis A virus, and with positive tuberculin skin tests (suggesting prior exposure and immune response to Mycobacterium tuberculosis). In contrast, there is evidence that children who have had attacks of bronchiolitis associated with respiratory syncytial virus (RSV) infection are more prone to the later development of asthma. Children hospitalized with this disease have a skewed ratio of cytokine production away from IFN-γ towards IL-4, the cytokine that induces TH2 responses. It is possible that infection by an organism that evokes a TH1 immune response early in life might reduce the likelihood of TH2 responses later in life and vice versa. It might be expected that exposure to

environmental pollution would worsen the expression of atopy and asthma. The best evidence shows the opposite effect, however. Children from the city of Halle in the former East Germany, which has severe air pollution, had a lower prevalence of atopy and asthma than an ethnically matched population from Munich, exposed to much cleaner air. This does not mean that polluted air is not bad for the lungs. The children from Halle had a higher overall prevalence of respiratory disease than their counterparts from Munich, but this was predominantly not allergic in origin.

While it is clear that allergy is related to allergen exposure, there is no evidence that the rising prevalence of allergy is due to any systematic change in allergen exposure. Nor is there any evidence that changes in diet can explain the increase in allergy in economically advanced populations.

 

 

 

 

 

 

Mast-cell activation has different effects on different tissues.

 

 

Most IgE is cell-bound and engages effector mechanisms of the immune system by different pathways from other antibody isotypes.

Most antibodies are found in body fluids and engage effector cells, through receptors specific for the Fc constant regions, only after binding specific antigen through the antibody variable regions. IgE, however, is an exception as it is captured by the high-affinity Fc receptor in the absence of bound antigen. This means that IgE is mostly found fixed in the tissues on mast cells that bear this receptor, as well as on circulating basophils and activated eosinophils.

The ligation of cell-bound IgE antibody by specific antigen triggers activation of these cells at the site of antigen entry into the tissues. The release of inflammatory lipid mediators, cytokines, and chemokines at sites of IgEtriggered reactions results in the recruitment of eosinophils and basophils to augment the type I response.

There are two types of IgE-binding Fc receptor. The first, Fc RI, is a high-affinity receptor of the immunoglobulin superfamily that binds IgE on mast cells, basophils, and activated eosinophils. When the cellbound IgE antibody is cross-linked by a specific antigen, Fc RI transduces an activating signal. High levels of IgE, such as those that exist in subjects with allergic diseases or parasite infections, can result in a marked increase in Fc RI on the surface of mast cells, enhanced sensitivity of such cells to activation by low concentrations of specific antigen, and markedly increased IgE-dependent release of chemical mediators and cytokines.

The second IgE receptor, Fc RII, usually known as CD23, is a C-type lectin and is structurally unrelated to Fc RI; it binds IgE with low affinity. CD23 is present on many different cell types, including B cells, activated T cells, monocytes, eosinophils, platelets, follicular dendritic cells, and some thymic epithelial cells. This receptor was thought to be crucial for the regulation of IgE antibody levels; however, knockout mouse strains lacking the CD23 gene show no major abnormality in the development of polyclonal IgE responses. However the CD23 knockout mice have demonstrated a role for CD23 in enhancing the antibody response to a specific antigen in the presence of that same antigen complexed with IgE. This antigen-specific, IgE-mediated enhancement of antibody responses fails to occur in mice lacking the CD23 gene. This demonstrates a role for CD23 on antigen-presenting cells in the capture of antigen by specific IgE.

 

Mast cells reside in tissues and orchestrate allergic reactions.

Mast cells were described by Ehrlich in the mesentery of rabbits and named Mastzellen ('fattened cells'). Like basophils, mast cells contain granules rich in acidic proteoglycans that take up basic dyes. However, in spite of this resemblance, and the similar range of mediators stored in these basophilic granules, mast cells are derived from a different myeloid lineage than basophils and eosinophils. Mast cells are highly specialized cells, and are prominent residents of mucosal and epithelial tissues in the vicinity of small blood vessels and postcapillary venules, where they are well placed to guard against invading pathogens. Mast cells are also found in subendothelial connective tissue. They home to tissues as agranular cells; their final differentiation, accompanied by granule formation, occurs after they have arrived in the tissues. The major growth factor for mast cells is stem-cell factor (SCF), which acts on the cell-surface receptor c-Kit. Mice with defective c-Kit lack differentiated mast cells and cannot make IgE-mediated inflammatory responses. This shows that such responses depend almost exclusively on mast cells. Mast cells express Fc RI constitutively on their surface and are activated when antigens cross-link IgE bound to these receptors. Degranulation occurs within seconds, releasing a variety of preformed inflammatory mediators. Among these are histamine a short-lived vasoactive amine that causes an immediate increase in local blood flow and vessel permeability and enzymes such as mast-cell chymase, tryptase, and serine esterases. These enzymes can in turn activate matrix metalloproteinases, which break down tissue matrix proteins, causing tissue destruction. Large amounts of tumor necrosis factor (TNF)-α are also released by mast cells after activation. Some comes from stores in mast-cell granules; some is newly synthesized by the activated mast cells themselves. TNF-α activates endothelial cells, causing increased expression of adhesion molecules, which promotes the influx of inflammatory leukocytes and lymphocytes into tissues. On activation, mast cells synthesize and release chemokines, lipid mediators such as leukotrienes and plateletactivating factor (PAF), and additional cytokines such as IL-4 and IL-13 which perpetuate the TH2 response. These mediators contribute to both the acute and the chronic inflammatory responses. The lipid mediators, in particular, act rapidly to cause smooth muscle contraction, increased vascular permeability, and mucus secretion, and also induce the influx and activation of leukocytes, which contribute to the late-phase response. The lipid mediators derive from membrane phospholipids, which are cleaved to release the precursor molecule arachidonic acid. This molecule can be modified by two pathways to give rise to prostaglandins, thromboxanes, and leukotrienes. The leukotrienes, especially C4, D4, and E4, are important in sustaining inflammatory responses in the tissues. Many anti-inflammatory drugs are inhibitors of arachidonic acid metabolism. Aspirin, for example, is an inhibitor of the enzyme cyclooxygenase and blocks the production of prostaglandins. IgE-mediated activation of mast cells thus orchestrates an important inflammatory cascade that is amplified by the recruitment of eosinophils, basophils, and TH2 lymphocytes. The physiological importance of this reaction is as a defense mechanism against certain types of infection. In allergy, however, the acute and chronic inflammatory reactions triggered by mast-cell activation have important pathophysiological consequences, as seen in the diseases associated with allergic responses to environmental antigens.

 

 

IgE antibody cross-linking on mast-cell surfaces leads to a rapid release of inflammatory mediators.

Mast cells are large cells found in connective tissue that can be distinguished by secretory granules containing many inflammatory mediators. They bind stably to monomeric IgE antibodies through the very highaffinity Fc receptor I. Antigen cross-linking of the bound IgE antibody molecules triggers rapid degranulation, releasing inflammatory mediators into the surrounding tissue. These mediators trigger local inflammation, which recruits cells and proteins required for host defense to sites of infection. These cells are also triggered during allergic reactions when allergens bind to IgE on mast cells.

 

Molecules released by mast cells on activation.

Mast cells produce a wide variety of biologically active proteins and other chemical mediators. The enzymes and toxic mediators listed in the first two rows are released from the preformed granules. The cytokines, chemokines, and lipid mediators are synthesized after activation.

Eosinophils are normally under tight control to prevent inappropriate toxic responses.

Eosinophils are granulocytic leukocytes that originate in bone marrow. They are so called because their granules, which contain arginine-rich basic proteins, are colored bright orange by the acidic stain eosin. Only very small numbers of these cells are normally present in the circulation; most eosinophils are found in tissues, especially in the connective tissue immediately underneath respiratory, gut, and urogenital epithelium, implying a likely role for these cells in defense against invading organisms. Eosinophils have two kinds of effector function. First, on activation they release highly toxic granule proteins and free radicals, which can kill microorganisms and parasites but can also cause significant tissue damage in allergic reactions. Second, activation induces the synthesis of chemical mediators such as prostaglandins, leukotrienes, and cytokines, which amplify the inflammatory response by activating epithelial cells, and recruiting and activating more eosinophils and leukocytes.

The activation and degranulation of eosinophils is strictly regulated, as their inappropriate activation would be very harmful to the host. The first level of control acts on the production of eosinophils by the bone marrow. Few eosinophils are produced in the absence of infection or other immune stimulation. But when TH2 cells are activated, cytokines such as IL-5 are released that increase the production of eosinophils in the bone marrow and their release into the circulation. However, transgenic animals overexpressing IL-5 have increased numbers of eosinophils (eosinophilia) in the circulation but not in their tissues, indicating that migration of eosinophils from the circulation into tissues is regulated separately, by a second set of controls. The key molecules in this case are CC chemokines Most of these cause chemotaxis of several types of leukocyte, but two are specific for eosinophils and have been named eotaxin 1 and eotaxin 2.

The eotaxin receptor on eosinophils, CCR3, is a member of the chemokine family of receptors. This receptor also binds the CC chemokines MCP-3, MCP-4, and RANTES, which also induce eosinophil chemotaxis. The eotaxins and these other CC chemokines also activate eosinophils. Identical or similar chemokines also stimulate mast cells and basophils. For example, eotaxin attracts basophils and causes their degranulation, and MCP-1, which binds to CCR2, similarly activates mast cells in both the presence or absence of antigen. MCP-1 can also promote the differentiation of naive TH0 cells to TH2 cells; TH2 cells also carry CCR3 and migrate toward eotaxin. These findings show that families of chemokines, as well as cytokines, can coordinate certain kinds of immune response.

A third set of controls regulates the state of eosinophil activation. In their nonactivated state, eosinophils do not express high-affinity IgE receptors and have a high threshold for release of their granule contents. After activation by cytokines and chemokines, this threshold drops, Fc RI is expressed, and the number of Fcγ receptors and complement receptors on the cell surface also increases. The eosinophil is now primed to carry out its effector activity, for example degranulation in response to antigen that cross-links specific IgE bound to Fc RI on the eosinophil surface.

The potential of eosinophils to cause tissue injury is illustrated by rare syndromes due to abnormally large numbers of eosinophils in the blood (hypereosinophilia). These syndromes are sometimes seen in association with T-cell lymphomas, in which unregulated IL-5 secretion drives a marked increase in the numbers of circulating eosinophils.

The clinical manifestations of hypereosinophilia are damage to the endocardium and to nerves, leading to heart failure and neuropathy, both thought to be caused by the toxic effects of eosinophil granule proteins.

Eosinophils can be detected easily in tissue sections by their bright refractile orange coloration.

In this light micrograph, a large number of eosinophils are seen infiltrating a tumor of Langherhans' cells known as Langerhans' cell histiocytosis. The tissue section is stained with hematoxylin and eosin; it is the eosin that imparts the characteristic orange color to the eosinophils.

Eosinophils secrete a range of highly toxic granule proteins and other inflammatory mediators.

Allergic reactions can be divided into an immediate response and a late-phase response.

A whealand-flare allergic reaction develops within a minute or two of superficial injection of antigen into the epidermis and lasts for up to 30 minutes. The reaction to an intracutaneous injection of house dust mite antigen is shown in the upper left panel and is labeled 'HDM;' the area labeled 'saline' shows the absence of any response to a control injection of saline solution. A more widespread edematous response, as shown in the upper right panel, develops approximately 8 hours later and can persist for some hours. Similarly, the response to an inhaled antigen can be divided into early and late responses (bottom panel). An asthmatic response in the lungs with narrowing of the airways caused by the constriction of bronchial smooth muscle can be measured as a fall in the forced expired volume of air in one second (FEV1). The immediate response peaks within minutes after antigen inhalation and then subsides.

Approximately 8 hours after antigen challenge, there is a late-phase response that also results in a fall in the FEV1.

The immediate response is caused by the direct effects on blood vessels and smooth muscle of rapidly metabolized mediators such as histamine released by mast cells. The late-phase response is caused by the effects of an influx of inflammatory leukocytes attracted by chemokines and other mediators released by mast cells during and after the immediate response.

Eosinophils and basophils cause inflammation and tissue damage in allergic reactions.

In a local allergic reaction, mast-cell degranulation and TH2 activation cause eosinophils to accumulate in large numbers and to become activated. Their continued presence is characteristic of chronic allergic inflammation and they are thought to be major contributors to tissue damage. Basophils are also present at the site of an inflammatory reaction. Basophils share a common stem-cell precursor with eosinophils; growth factors for basophils are very similar to those for eosinophils and include IL-3, IL-5, and GMCSF.

There is evidence for reciprocal control of the maturation of the stem-cell population into basophils or eosinophils. For example, transforming growth factor (TGF)-β in the presence of IL-3 suppresses eosinophil differentiation and enhances that of basophils. Basophils are normally present in very low numbers in the circulation and seem to have a similar role to eosinophils in defense against pathogens. Like eosinophils, they are recruited to the sites of allergic reactions. Basophils express Fc RI on the cell surface and, on activation by cytokines or antigen, they release histamine and IL-4 from the basophilic granules after which they are named.

Eosinophils, mast cells, and basophils can interact with each other. Eosinophil degranulation releases major basic protein, which in turn causes degranulation of mast cells and basophils. This effect is augmented by any of the cytokines that affect eosinophil and basophil growth, differentiation, and activation, such as IL-3, IL-5, and GM-CSF.

An allergic reaction is divided into an immediate response and a late-phase response.

The inflammatory response after IgE-mediated mast-cell activation occurs as an immediate reaction, starting within seconds, and a late reaction, which takes up to 8 12 hours to develop. These reactions can be distinguished clinically The immediate reaction is due to the activity of histamine, prostaglandins, and other preformed or rapidly synthesized mediators that cause a rapid increase in vascular permeability and the contraction of smooth muscle. The late-phase reaction is caused by the induced synthesis and release of mediators including leukotrienes, chemokines, and cytokines from the activated mast cells. These recruit other leukocytes, including eosinophils and TH2 lymphocytes, to the site of inflammation. Although the late-phase reaction is clinically less marked than the immediate response, it is associated with a second phase of smooth muscle contraction, sustained edema, and the development of one of the cardinal features of allergic asthma: airway hyperreactivity to non-specific bronchoconstrictor stimuli such as histamine and methacholine.

The late-phase reaction is an important cause of much serious long-term illness, as for example in chronic asthma. This is because the late reaction induces the recruitment of inflammatory leukocytes, especially eosinophils and TH2 lymphocytes, to the site of the allergen-triggered mast-cell response. This late response can easily convert into a chronic inflammatory response if antigen persists and stimulates allergen-specific TH2 cells, which in turn promote eosinophilia and further IgE production.

 

The clinical effects of allergic reactions vary according to the site of mast-cell activation.

When reexposure to allergen triggers an allergic reaction, the effects are focused on the site at which mast-cell degranulation occurs. In the immediate response, the preformed mediators released are short-lived, and their potent effects on blood vessels and smooth muscles are therefore confined to the vicinity of the activated mast cell. The more sustained effects of the late-phase response are also focused on the site of initial allergen-triggered activation, and the particular anatomy of this site may determine how readily the inflammation can be resolved. Thus, the clinical syndrome produced by an allergic reaction depends critically on three variables: the amount of allergenspecific IgE present; the route by which the allergen is introduced; and the dose of allergen. If an allergen is introduced directly into the bloodstream or is rapidly absorbed from the gut, the connective tissue mast cells associated with all blood vessels can become activated. This activation causes a very dangerous syndrome called systemic anaphylaxis. Disseminated mast-cell activation has a variety of potentially fatal effects: the widespread increase in vascular permeability leads to a catastrophic loss of blood pressure; airways constrict, causing  difficulty in breathing; and swelling of the epiglottis can cause suffocation. This potentially fatal syndrome is called anaphylactic shock. It can occur if drugs are administered to people who have IgE specific for that drug, or after an insect bite in individuals allergic to insect venom. Some foods, for example peanuts or brazil nuts, can cause systemic anaphylaxis in susceptible individuals. This syndrome can be rapidly fatal but can usually be controlled by the immediate injection of epinephrine, which relaxes the smooth muscle and inhibits the cardiovascular effects of anaphylaxis.

The most frequent allergic reactions to drugs occur with penicillin and its relatives. In people with IgE antibodies against penicillin, administration of the drug by injection can cause anaphylaxis and even death. Great care should be taken to avoid giving a drug to patients with a past history of allergy to that drug or one that is closely related structurally. Penicillin acts as a hapten; it is a small molecule with a highly reactive β-lactam ring that is crucial for its antibacterial activity. This ring reacts with amino groups on host proteins to form covalent conjugates. When penicillin is ingested or injected, it forms conjugates with self proteins, and the penicillin-modified self peptides can provoke a TH2 response in some individuals. These TH2 cells then activate penicillin-binding B cells to produce IgE antibody to the penicillin hapten. Thus, penicillin acts both as the B-cell antigen and, by modifying self peptides, as the T-cell antigen. When penicillin is injected intravenously into an allergic individual, the penicillinmodified proteins can cross-link IgE molecules on the mast cells and cause anaphylaxis.

 

Allergen inhalation is associated with the development of rhinitis and asthma.

Inhalation is the most common route of allergen entry. Many people have mild allergies to inhaled antigens, manifesting as sneezing and a runny nose. This is called allergic rhinitis, and results from the activation of mucosal mast cells beneath the nasal epithelium by allergens such as pollens that release their protein contents, which can then diffuse across the mucus membranes of the nasal passages. Allergic rhinitis is characterized by intense itching and sneezing, local edema leading to blocked nasal passages, a nasal discharge, which is typically rich in eosinophils, and irritation of the nose as a result of histamine release. A similar reaction to airborne allergens deposited on the conjunctiva of the eye is called allergic conjunctivitis. Allergic rhinitis and conjunctivitis are commonly caused by environmental allergens that are only present during certain seasons of the year. For example, hay fever is caused by a variety of allergens, including certain grass and tree pollens. Autumnal symptoms may be caused by weed pollen, such as that of ragweed. These reactions are annoying but cause little lasting damage.

A more serious syndrome is allergic asthma, which is triggered by allergen-induced activation of submucosal mast cells in the lower airways. This leads within seconds to bronchial constriction and increased secretion of fluid and mucus, making breathing more difficult by trapping inhaled air in the lungs. Patients with allergic asthma often need treatment, and asthmatic attacks can be life-threatening. An important feature of asthma is chronic inflammation of the airways, which is characterized by the continued presence of increased numbers of TH2 lymphocytes, eosinophils, neutrophils, and other leukocytes. Although allergic asthma is initially driven by a response to a specific allergen, the subsequent chronic inflammation seems to be perpetuated even in the apparent absence of further exposure to allergen. The airways become characteristically hyperreactive and factors other than reexposure to antigen can trigger asthma attacks. For example, the airways of asthmatics characteristically show hyperresponsiveness to environmental chemical irritants such as cigarette smoke and sulfur dioxide; viral or, to a lesser extent, bacterial respiratory tract infections can exacerbate the disease by inducing a TH2-dominated local response.

 

The acute response in allergic asthma leads to TH2-mediated chronic inflammation of the airways.

In sensitized individuals, cross-linking of specific IgE on the surface of mast cells by an inhaled allergen triggers them to secrete inflammatory mediators, causing increased vascular permeability, contraction of bronchial smooth muscle, and increased mucus secretion. There is an influx of inflammatory cells, including eosinophils and TH2 cells, from the blood. Activated mast cells and TH2 cells secrete cytokines that augment eosinophil activation and degranulation, which causes further tissue injury and the entry of more inflammatory cells. The result is chronic inflammation, which can cause irreversible damage to the airways.

 

Skin allergy is manifest as urticaria or chronic eczema.

 

 

 

 

The same dichotomy between immediate and delayed responses is seen in cutaneous allergic responses. The skin forms an effective barrier to the entry of most allergens but it can be breached by local injection of small amounts of allergen, for example by a stinging insect. The entry of allergen into the epidermis or dermis causes a localized

allergic reaction. Local mast-cell activation in the skin leads immediately to a local increase in vascular permeability, which causes extravasation of fluid and swelling. Mast-cell activation also stimulates the release of chemicals from local nerve endings by a nerve axon reflex, causing the vasodilation of surrounding cutaneous blood vessels, which causes redness of the surrounding skin. The resulting skin lesion is called a wheal-and-flare reaction. About 8 hours later, a more widespread and sustained edematous response appears in some individuals as a consequence of the latephase response. A disseminated form of the wheal-and-flare reaction, known as urticaria or hives, sometimes appears when ingested allergens enter the bloodstream and reach the skin. Histamine released by mast cells activated by allergen in the skin causes large, itchy, red swellings of the skin.

 

 

Allergists take advantage of the immediate response to test for allergy by injecting minute amounts of potential allergens into the epidermal layer of the skin. Although the reaction after the administration of antigen by intraepidermal injection is usually very localized, there is a small risk of inducing systemic anaphylaxis. Another

standard test for allergy is to measure levels of IgE antibody specific for a particular allergen in a sandwich ELISA  Although acute urticaria is commonly caused by allergens, the causes of chronic urticaria, in which the urticarial rash can recur over long periods, are less well understood. In up to a third of cases, it seems likely that chronic urticaria is an autoimmune disease caused by autoantibodies against the α chain of Fc RI.

 

 

This is an example of a type II hypersensitivity reaction in which an autoantibody against a cellular receptor triggers cellular activation, in this case

causing mast-cell degranulation with resulting urticaria.

 

 

A more prolonged inflammatory response is sometimes seen in the skin, most often in atopic children. They develop a persistent skin rash called eczema or atopic dermatitis, due to a chronic inflammatory response similar to that seen

in the bronchial walls of patients with asthma. The etiology of eczema is not well understood. TH2 cells and IgE are involved, and it usually clears in adolescence, unlike rhinitis and asthma, which can persist throughout life.

 

Allergy to foods causes symptoms limited to the gut and systemic reactions.

When an allergen is eaten, two types of allergic response are seen. Activation of mucosal mast cells associated with the gastrointestinal tract leads to transepithelial fluid loss and smooth muscle contraction, causing diarrhea and vomiting. For reasons that are not understood, connective tissue mast cells in the dermis and subcutaneous tissues can also be activated after ingestion of allergen, presumably by allergen that has been absorbed into the bloodstream, and this results in urticaria. Urticaria is a common reaction when penicillin is given orally to a patient who already has penicillin-specific IgE antibodies. Ingestion of food allergens can also lead to the development of generalized anaphylaxis, accompanied by cardiovascular collapse and acute asthmatic symptoms. Certain foods, most importantly peanuts, tree nuts, and shellfish, are particularly associated with this type of life-threatening response.

 

Summary.

The allergic response to innocuous antigens reflects the pathophysiological aspects of a defensive immune response whose physiological role is to protect against helminthic parasites. It is triggered by antigen binding to IgE antibodies bound to the high-affinity IgE receptor Fc RI on mast cells. Mast cells are strategically distributed beneath the mucosal surfaces of the body and in connective tissue. Antigen cross-linking the IgE on their surface causes them to release large amounts of inflammatory mediators. The resulting inflammation can be divided into early events, characterized by short-lived mediators such as histamine, and later events that involve leukotrienes, cytokines, and chemokines, which recruit and activate eosinophils and basophils. The late phase of this response can evolve into chronic inflammation, characterized by the presence of effector T cells and eosinophils, which is most clearly seen in chronic allergic asthma.

Hypersensitivity diseases.

Immunological responses involving IgG antibodies or specific T cells can also cause adverse hypersensitivity reactions. Although these effector arms of the immune response normally participate in protective immunity to infection, they occasionally react with noninfectious antigens to produce acute or chronic hypersensitivity reactions.

We will describe common examples of such reactions in this part of the chapter.

Innocuous antigens can cause type II hypersensitivity reactions in susceptible individuals by binding to the surfaces of circulating blood cells.

Antibody-mediated destruction  f red blood cells (hemolytic anemia) or platelets (thrombocytopenia) is an uncommon side-effect associated with the intake of certain drugs such as the antibiotic penicillin, the anti-cardiac arrhythmia drug quinidine, or the antihypertensive agent methyldopa. These are examples of type II hypersensitivity reactions in which the drug binds to the cell surface and serves as a target for anti-drug IgG antibodies that cause destruction of the cell. The anti-drug antibodies are made in only a minority of individuals and it is not clear why these individuals make them. The cell-bound antibody triggers clearance of the cell from the circulation, predominantly by tissue macrophages in the spleen, which bear Fcγ receptors.

Systemic disease caused by immune complex formation can follow the administration of large quantities of poorly catabolized antigens.

Type III hypersensitivity reactions can arise with soluble antigens. The pathology is caused by the deposition of antigen:antibody aggregates or immune complexes at certain tissue sites. Immune complexes are generated in all antibody responses but their pathogenic potential is determined, in part, by their size and the amount, affinity, and isotype of the responding antibody. Larger aggregates fix complement and are readily cleared from the circulation by the mononuclear phagocytic system. The small complexes that form at antigen excess, however, tend to deposit in blood vessel walls. There they can ligate Fc receptors on leukocytes, leading to leukocyte activation and tissue injury. A local type III hypersensitivity reaction can be triggered in the skin of sensitized individuals who possess IgG antibodies against the sensitizing antigen. When antigen is injected into the skin, circulating IgG antibody that has diffused into the tissues forms immune complexes locally. The immune complexes bind Fc receptors on mast cells and other leukocytes, which creates a local inflammatory response with increased vascular permeability. The enhanced vascular permeability allows fluid and cells, especially polymorphonuclear leukocytes, to enter the site

from the local vessels. This reaction is called an Arthus reaction. The immune complexes also activate complement, releasing C5a, which contributes to the inflammatory reaction by ligating C5a receptors on leukocytes . This causes their activation and chemotactic attraction to the site of inflammation. The Arthus reaction is absent in mice lacking the α or γ chain of the FcγRIII receptor (CD16) on mast cells, but remains largely unperturbed in complementdeficient mice, showing the primary importance of FcγRIII in triggering inflammatory responses via immune complexes.

A systemic type III hypersensitivity reaction, known as serum sickness, can result from the injection of large quantities of a poorly catabolized foreign antigen. This illness was so named because it frequently followed the administration of therapeutic horse antiserum. In the preantibiotic era, antiserum made by immunizing horses was often used to treat pneumococcal pneumonia; the specific anti-pneumococcal antibodies in the horse serum would help the patient to clear the infection. In much the same way, antivenin (serum from horses immunized with snake venoms) is still used today as a source of neutralizing antibodies to treat people suffering from the bites of poisonous snakes.

Serum sickness occurs 7-10 days after the injection of the horse serum, an interval that corresponds to the time required to mount a primary immune response that switches from IgM to IgG antibody against the foreign antigens in horse serum. The clinical features of serum sickness are chills, fever, rash, arthritis, and sometimes glomerulonephritis. Urticaria is a prominent feature of the rash, implying a role for histamine derived from mast-cell degranulation. In this case the mast-cell degranulation is triggered by the ligation of cellsurface FcγRIII by IgGcontaining immune complexes.

The course of serum sickness is illustrated. The onset of disease coincides with the development of antibodies against the abundant soluble proteins in the foreign serum; these antibodies form immune complexes with their antigens throughout the body. These immune complexes fix complement and can bind to and activate leukocytes

bearing Fc and complement receptors; these in turn cause widespread tissue injury. The formation of immune complexes causes clearance of the foreign antigen and so serum sickness is usually a self-limiting disease. Serum sickness after a second dose of antigen follows the kinetics of a secondary antibody response and the onset of disease occurs typically within a day or two. Serum sickness is nowadays seen after the use of anti-lymphocyte globulin, employed as an immunosuppressive agent in transplant recipients, and also, rarely, after the administration of streptokinase, a bacterial enzyme that is used as a thrombolytic agent to treat patients with a myocardial infarction or heart attack.

A similar type of immunopathological response is seen in two other situations in which antigen persists. The first is when an adaptive antibody response fails to clear an infectious agent, for example in subacute bacterial endocarditis or chronic viral hepatitis. In this situation, the multiplying bacteria or viruses are continuously generating new antigen in the presence of a persistent antibody response that fails to eliminate the organism. Immune complex disease ensues, with injury to small blood vessels in many tissues and organs, including the skin, kidneys, and nerves.

Immune complexes also form in autoimmune diseases such as systemic lupus erythematosus where, because the antigen persists, the deposition of immune complexes continues, and serious disease can result.

Some inhaled allergens provoke IgG rather than IgE antibody responses, perhaps because they are present at relatively high levels in inhaled air. When a person is reexposed to high doses of such inhaled antigens, immune complexes form in the alveolar wall of the lung. This leads to the accumulation of fluid, protein, and cells in the alveolar wall, slowing blood-gas interchange and compromising lung function. This type of reaction occurs in certain occupations such as farming, where there is repeated exposure to hay dust or mold spores. The disease that results is therefore called farmer's lung (VIDEO). If exposure to antigen is sustained, the alveolar membranes can become permanently damaged.

The deposition of immune complexes in local tissues causes a local inflammatory response known as an Arthus reaction (type III hypersensitivity reaction).

In individuals who have already made IgG antibody against an antigen, the same antigen injected into the skin forms immune complexes with IgG antibody that has diffused out of the capillaries. Because the dose of antigen is low, the immune complexes are only formed close to the site of injection, where they activate mast cells bearing Fcγ receptors (FcγRIII). As a result of mast-cell activation, inflammatory cells invade the site, and blood vessel permeability and blood flow are increased. Platelets also accumulate inside the vessel at the site, ultimately leading to vessel occlusion.

Serum sickness is a classic example of a transient immune complex-mediated syndrome.

An injection of a foreign protein or proteins leads to an antibody response. These antibodies form immune complexes with the circulating foreign proteins. The complexes are deposited in small vessels and activate complement and phagocytes, inducing fever and the symptoms of vasculitis, nephritis, and arthritis. All these effects are transient and resolve when the foreign protein is cleared.

 

Delayed-type hypersensitivity reactions are mediated by TH1 cells and CD8 cytotoxic T cells.

Unlike the immediate hypersensitivity reactions described so far, which are mediated by antibodies, delayed-type hypersensitivity or type IV hypersensitivity reactions are mediated by antigen-specific effector T cells. These function in essentially the same way as during a response to an infectious pathogen. The causes and consequences of some syndromes in which type IV hypersensitivity responses predominate are listed 

These responses can be transferred between experimental animals by purified T cells or cloned T-cell lines.

Type IV hypersensitivity responses.

These reactions are mediated by T cells and all take some time to develop. They can be grouped into three syndromes, according to the route by which antigen passes into the body. In delayed-type hypersensitivity the antigen is injected into the skin; in contact hypersensitivity it is absorbed into the skin; and in gluten-sensitive enteropathy it is absorbed by the gut.

 

The prototypic delayed-type hypersensitivity reaction is an artifact of modern medicine the tuberculin test This is used to determine whether an individual has previously been infected with Mycobacterium tuberculosis. Small amounts of tuberculin a complex mixture of peptides and carbohydrates derived from M. tuberculosis are injected intradermally. In individuals who have previously been exposed to the bacterium, either by infection with the pathogen or by immunization with BCG, an attenuated form of M. tuberculosis, a local T cell-mediated inflammatory reaction evolves over 24-72 hours. The response is mediated by

TH1 cells, which enter the site of antigen injection, recognize complexes of peptide:MHC class II molecules on antigen-presenting cells, and release inflammatory cytokines, such as IFN-γ and TNF-β. The cytokines stimulate the expression of adhesion molecules on endothelium and increase local blood vessel permeability, allowing plasma and accessory cells to enter the site; this causes a visible swelling. Each of these phases takes several hours and so the fully developed response appears only 24-48 hours after challenge. The cytokines produced by the activated TH1 cells and their actions are shown.

 

 

 

Blistering skin lesions on hand of patient with poison ivy contact dermatitis.

Langerhans' cells can take up antigen in the skin and migrate to lymphoid organs where they present it to T cells.

Langerhans' cells can ingest antigen by several means, but have no co-stimulatory activity. In the presence of infection, they take up antigen locally in the skin and then migrate to the lymph nodes. There they differentiate into dendritic cells that can no longer ingest antigen but now have co-stimulatory activity. The rash produced by contact with poison ivy is caused by a T-cell response to a chemical in the poison ivy leaf called pentadecacatechol. This compound is lipid-soluble and can therefore cross the cell membrane and modify intracellular proteins. These modified proteins generate modified peptides within the cytosol, which are translocated into the endoplasmic reticulum and are delivered to the cell surface by MHC class I molecules. These are recognized by CD8 T cells, which can cause damage either by killing the eliciting cell or by secreting cytokines such as IFN-γ. The well-studied chemical picryl chloride produces a CD4 T-cell hypersensitivity reaction. It modifies extracellular self proteins, which are then processed by the exogenous pathway  into modified self peptides that bind to self MHC class II molecules and are recognized by TH1 cells. When sensitized TH1 cells recognize these complexes they can produce extensive inflammation by activating macrophages. As the chemicals in these examples are delivered by contact with the skin, the rash that follows is called a contact hypersensitivity reaction.

 

Some insect proteins also elicit delayed-type hypersensitivity response. However, the early phases of the host reaction to an insect bite are often IgE-mediated or the result of the direct effects of insect venoms. Important delayed-type hypersensitivity responses to divalent cations such as nickel have also been observed. These divalent cations can alter the conformation or the peptide binding of MHC class II molecules, and thus provoke a T-cell response. Finally, although this section has focused on the role of T cells in inducing delayed-type hypersensitivity reactions, there is evidence that antibody and complement may also play a part. Mice deficient in B cells, antibody, or complement show impaired contact hypersensitivity reactions. These requirements for B cells, antibody, and complement may reflect their role in the early steps of the elicitation of these reactions.

 

Summary.

Hypersensitivity diseases reflect normal immune mechanisms directed against innocuous antigens. They can be mediated by IgG antibodies bound to modified cell surfaces, or by complexes of antibodies bound to poorly catabolized antigens, as occurs in serum sickness. Hypersensitivity reactions mediated by T cells can be activated by modified self proteins, or by injected proteins such as those in the mycobacterial extract tuberculin. These T cellmediated responses require the induced synthesis of effector molecules and develop more slowly, which is why they are termed delayed-type hyper-sensitivity. In some people, immune responses to otherwise innocuous antigens produce allergic or hypersensitivity reactions upon reexposure to the same antigen. Most allergies involve the production of IgE antibody to common environmental allergens. Some people are intrinsically prone to making IgE antibodies against many allergens, and such people are said to be atopic. IgE production is driven by antigen-specific TH2 cells, which are initially primed in the presence of a burst of IL-4 released by specialized T cells early in the immune response. The IgE produced binds to the high-affinity IgE receptor Fc RI on mast cells, basophils, and activated eosinophils. The physiological role of this system is to provide front-line defense against parasite pathogens but, in economically developed societies in which parasitic infections are uncommon, it is almost always involved in allergic reactions. Eosinophils and specific effector T cells have an extremely important role in chronic allergic inflammation, which is the major cause of the chronic morbidity of asthma. Antibodies of other isotypes and antigen-specific effector T cells contribute to hypersensitivity to other antigens.

 

 

Immune disorders: hypersensitivity and autoimmune diseases (279.5–6)     Type I/allergy/atopy (IgE) Foreign Atopic dermatitis · Allergic urticaria · Hay fever · Allergic asthma · Anaphylaxis · Food allergy (Milk, Egg, Peanut, Tree nut, Seafood, Soy, Wheat), Penicillin allergy Autoimmune none Type II/ADCC (IgM , IgG) Foreign Pernicious anemia · Hemolytic disease of the newborn Autoimmune Cytotoxic Autoimmune hemolytic anemia · Idiopathic thrombocytopenic purpura  · Bullous pemphigoid  · Pemphigus vulgaris · Rheumatic fever · Goodpasture's syndrome "Type 5"/receptor   Graves' disease · Myasthenia gravis Type III (Immune complex) Foreign Henoch–Schönlein purpura · Hypersensitivity vasculitis · Reactive arthritis · Farmer's lung · Post-streptococcal glomerulonephritis · Serum sickness · Arthus reaction Autoimmune Systemic lupus erythematosus · Subacute bacterial endocarditis · Rheumatoid arthritis Type IV/cell-mediated (T-cells) Foreign Allergic contact dermatitis · Mantoux test Autoimmune Diabetes mellitus type 1 · Hashimoto's thyroiditis · Guillain–Barré syndrome  · Multiple sclerosis  · Coeliac disease · Giant-cell arteritis GVHD Transfusion-associated graft versus host disease Unknown/ multiple Foreign Hypersensitivity pneumonitis (Allergic bronchopulmonary aspergillosis) · Transplant rejection · Latex allergy (I+IV) Autoimmune Sjögren's syndrome · Autoimmune hepatitis · Autoimmune polyendocrine syndrome (APS1, APS2) · Autoimmune adrenalitis · Systemic autoimmune disease

PSEUDOALLERGY

Pseudoallergy is a condition named for its similar presentation to a true allergy, though due to different causes.

It may be due to alterations in the metabolism of histamine.^[

It can be the cause of some forms of food intolerance.

Food intolerance or non-allergic food hypersensitivity is a term used widely for varied physiological responses associated with a particular food, or compound found in a range of foods.

Food intolerance is a detrimental reaction, often delayed, to a food, beverage, food additive, or compound found in foods that produces symptoms in one or more body organs and systems, but it is not a true food allergy. A true food allergy requires the presence of Immunoglobin E (IgE) antibodies against the food, and a food intolerance does not.

Food intolerances can be classified according to their mechanism. Intolerance can result from the absence of specific chemicals or enzymes needed to digest a food substance, as in hereditary fructose intolerance. It may be a result of an abnormality in the body's ability to absorb nutrients, as occurs in fructose malabsorption. Food intolerance reactions can occur to naturally occurring chemicals in foods, as in salicylate sensitivity. Drugs sourced from plants, such as aspirin, can also cause these kinds of reactions. Finally, it may be the result of non-IgE-mediated immune responses.

Definitions

Non-allergic food hypersensitivity is the medical name for food intolerance, loosely referred to as food hypersensitivity, or previously as pseudo-allergic reactions. Non-allergic food hypersensitivity should not be confused with true food allergies.

Food intolerance reactions can include pharmacologic, metabolic, and gastro-intestinal responses to foods or food compounds. Food intolerance does not include either psychological responses or foodborne illness.

A non-allergic food hypersensitivity is an abnormal physiological response. It can be difficult to determine the poorly tolerated substance as reactions can be delayed, dose-dependant, and a particular reaction-causing compound may be found in many foods.

·                  Metabolic food reactions are due to inborn or acquired errors of metabolism of nutrients, such as in diabetes mellitus, lactase deficiency, phenylketonuria and favism.

·                  Pharmacological reactions are generally due to low-molecular-weight chemicals which occur either as natural compounds, such as salicylates and amines, or to food additives, such as preservatives, colouring, emulsifiers and taste enhancers. These chemicals are capable of causing drug-like (biochemical) side effects in susceptible individuals.^[5]

·                  Gastro-intestinal reactions can be due to malabsorption or other GI Tract abnormalities.

·                  Immunological responses are mediated by non-IgE immunoglobulins, where the immune system recognises a particular food as a foreign body.

·                  Toxins may either be present naturally in food, be released by bacteria, or be due to contamination of food products.^[Toxic food reactions are caused by the direct action of a food or substance without immune involvement.

·                  Psychological reactions involve manifestation of clinical symptoms caused not by food but by emotions associated with food. These symptoms do not occur when the food is given in an unrecognisable form.^[5]

Elimination diets are useful to assist in the diagnosis of food intolerance. There are specific diagnostic tests for certain food intolerances.

Signs and symptoms

Non-IgE-mediated food hypersensitivity (food intolerance) is more chronic, less acute, less obvious in its presentation, and often more difficult to diagnose than a food allergy.^[8] Symptoms of food intolerance vary greatly, and can be mistaken for the symptoms of a food allergy. While true allergies are associated with fast-acting immunoglobulin IgE responses, it can be difficult to determine the offending food causing a food intolerance because the response generally takes place over a prolonged period of time. Thus the causative agent and the response are separated in time, and may not be obviously related. Food intolerance symptoms usually begin about half an hour after eating or drinking the food in question, but sometimes symptoms may delayed up to 48 h.

Food intolerance can present with symptoms affecting the skin, respiratory tract, gastrointestinal tract (GIT) either individually or in combination. On the skin may include skin rashes, urticaria (hives), angioedema,  dermatitis, and eczema. Respiratory tract symptoms can include nasal congestion, sinusitis, pharyngeal irritations, asthma and an unproductive cough. GIT symptoms include mouth ulcers, abdominal cramp, nausea, gas, intermittent diarrhea, constipation, irritable bowel syndrome, and may include anaphylaxis.

Food intolerance has been found associated with; irritable bowel syndrome and inflammatory bowel disease, chronic constipation, chronic hepatitis C infection, eczema,^[ NSAID intolerance, respiratory complaints, including asthma, rhinitis and headache, functional dyspepsia, eosinophilic esophagitis and ENT illnesses.

Causes

Reactions to chemical components of the diet are more common than true food allergies. They are caused by various organic chemicals occurring naturally in a wide variety of foods, both of animal and vegetable origin more often than to food additives, preservatives, colourings and flavourings, such as sulfites or dyes. Both natural and artificial ingredients may cause adverse reactions in sensitive people if consumed in sufficient amount, the degree of sensitivity varying between individuals.

Pharmacological responses to naturally occurring compounds in food, or chemical intolerance, can occur in individuals from both allergic and non-allergic family backgrounds. Symptoms may begin at any age, and may develop quickly or slowly. Triggers may range from a viral infection or illness to environmental chemical exposure. It occurs more commonly in women, which may be because of hormone differences, as many food chemicals mimic hormones.

A deficiency in digestive enzymes can also cause some types of food intolerances. Lactose intolerance is a result of the body not producing sufficient lactase to digest the lactose in milk; dairy foods which are lower in lactose, such as cheese, are less likely to trigger a reaction in this case. Another carbohydrate intolerance caused by enzyme deficiency is hereditary fructose intolerance.

Celiac disease, an autoimmune disorder caused by an immune response to the protein gluten, results in gluten intolerance and can lead to temporary lactose intolerance.

The most widely distributed naturally occurring food chemical capable of provoking reactions is salicylate, although tartrazine and benzoic acid are well recognised in susceptible individuals. Benzoates and salicylates occur naturally in many different foods, including fruits, juices, vegetables, spices, herbs, nuts, tea, wines, and coffee. Salicylate sensitivity causes reactions to not only aspirin and NSAIDs but also foods in which salicylates naturally occur, such as cherries.

Other natural chemicals which commonly cause reactions and cross reactivity include amines, nitrates, sulphites and some antioxidants. Chemicals involved in aroma and flavour are often suspect.

The classification or avoidance of foods based on botanical families bears no relationship to their chemical content and is not relevant in the management of food intolerance.

Salicylate-containing foods include apples, citrus fruits, strawberries, tomatoes, and wine, while reactions to chocolate, cheese, bananas, avocado, tomato or wine point to amines as the likely food chemical. Thus exclusion of single foods does not necessarily identify the chemical responsible as several chemicals can be present in a food, the patient may be sensitive to multiple food chemicals and reaction more likely to occur when foods containing the triggering substance are eaten in a combined quantity that exceeds the patient's sensitivity thresholds. People with food sensitivities have different sensitivity thresholds, and so more sensitive people will react to much smaller amounts of the substance.

Diagnosis

Diagnosis of food intolerance can include hydrogen breath testing for lactose intolerance and fructose malabsorption, professionally supervised elimination diets, and ELISA testing for IgG-mediated immune responses to specific foods. It is important to be able to distinguish between food allergy, food intolerance, and autoimmune disease in the management of these disorders.^[43] Non-IgE-mediated intolerance is more chronic, less acute, less obvious in its clinical presentation, and often more difficult to diagnose than allergy, as skin tests and standard immunological studies are not helpful.^[8] Elimination diets must remove all poorly tolerated foods, or all foods containing offending compounds. Clinical investigation is generally undertaken only for more serious cases, as for minor complaints which do not significantly limit the person's lifestyle the cure may be more inconvenient than the problem.

The Hemocode Food Intolerance System and Rocky Mountain Analytical Food Allergy Test are unvalidated yet heavily marketed examples of ELISA testing of IgG4 to foods. IgG4 against foods indicates that the person has been repeatedly exposed to food proteins recognized as foreign by the immune system. However, its presence should not be considered a factor which induces intolerance. Food-specific IgG4 does not indicate food allergy or intolerance, but rather a normal physiological response of the immune system after exposure to food components. Although elimination of foods based on IgG-4 testing in IBS patients resulted in an improvement in symptoms, the positive effects of food elimination were more likely due to wheat and milk elimination than IgG-4 test-determined factors.^[46] The IgG-4 test specificity is questionable as healthy individuals with no symptoms of food intolerance also test positive for IgG-4 to several foods.

Diagnosis is made using medical history and cutaneous and serological tests to exclude other causes, but to obtain final confirmation a Double Blind Controlled Food Challenge must be performed. Treatment can involve long-term avoidance, or if possible re-establishing a level of tolerance.

The antigen leukocyte cellular antibody test (ALCAT) has been commercially promoted as an alternative, but has not been reliably shown to be of clinical value.

Prevention

There is emerging evidence from studies of cord bloods that both sensitization and the acquisition of tolerance can begin in pregnancy, however the window of main danger for sensitization to foods extends prenatally, remaining most critical during early infancy when the immune system and intestinal tract are still maturing. There is no conclusive evidence to support the restriction of dairy intake in the maternal diet during pregnancy in order to prevent. This is generally not recommended since the drawbacks in terms of loss of nutrition can out-weigh the benefits. However, further randomised, controlled trials are required to examine if dietary exclusion by lactating mothers can truly minimize risk to a significant degree and if any reduction in risk is out-weighed by deleterious impacts on maternal nutrition.

A Cochrane review has concluded feeding with a soy formula cannot be recommended for prevention of allergy or food intolerance in infants. Further research may be warranted to determine the role of soy formulas for prevention of allergy or food intolerance in infants unable to be breast fed with a strong family history of allergy or cow's milk protein intolerance. In the case of allergy and celiac disease others recommend a dietary regimen is effective in the prevention of allergic diseases in high-risk infants, particularly in early infancy regarding food allergy and eczema. The most effective dietary regimen is exclusively breastfeeding for at least 4–6 months or, in absence of breast milk, formulas with documented reduced allergenicity for at least the first 4 months, combined with avoidance of solid food and cow's milk for the first 4 months.

Management

Individuals can try minor changes of diet to exclude foods causing obvious reactions, and for many this may be adequate without the need for professional assistance. For reasons mentioned above foods causing problems may not be so obvious since food sensitivities may not be noticed for hours or even days after one has digested food. Persons unable to isolate foods and those more sensitive or with disabling symptoms should seek expert medical and dietitian help. The dietetic department of a teaching hospital is a good start. (see links below)

Guidance can also be given to your general practitioner to assist in diagnosis and management. Food elimination diets have been designed to exclude food chemicals likely to cause reactions and foods commonly causing true allergies and those foods where enzyme deficiency cause symptoms. These elimination diets are not everyday diets but intended to isolate problem foods and chemicals. Avoidance of foods with additives is also essential in this process.

Individuals and practitioners need to be aware that during the elimination process patients can display aspects of food addiction, masking, withdrawals, and further sensitization and intolerance. Those foods that an individual considers as 'must have every day' are suspect addictions, this includes tea, coffee, chocolate and health foods and drinks, as they all contain food chemicals. Individuals are also unlikely to associate foods causing problems because of masking or where separation of time between eating and symptoms occur. The elimination process can overcome addiction and unmask problem foods so that the patients can associate cause and effect.

It takes around five days of total abstinence to unmask a food or chemical, during the first week on an elimination diet withdrawal symptoms can occur but it takes at least two weeks to remove residual traces. If symptoms have not subsided after six weeks, food intolerance is unlikely to be involved and a normal diet should be restarted. Withdrawals are often associated with a lowering of the threshold for sensitivity which assists in challenge testing, but in this period individuals can be ultra-sensitive even to food smells so care must be taken to avoid all exposures.

After two or more weeks if the symptoms have reduced considerably or gone for at least five days then challenge testing can begin. This can be carried out with selected foods containing only one food chemical, so as to isolate it if reactions occur. In Australia, purified food chemicals in capsule form are available to doctors for patient testing. These are often combined with placebo capsules for control purposes. (See link below.) This type of challenge is more definitive. New challenges should only be given after 48 hours if no reactions occur or after five days of no symptoms if reactions occur.

Once all food chemical sensitivities are identified a dietitian can prescribe an appropriate diet for the individual to avoid foods with those chemicals. Lists of suitable foods are available from various hospitals and patient support groups can give local food brand advice. A dietitian will ensure adequate nutrition is achieved with safe foods and supplements if need be.

Over a period of time it is possible for individuals avoiding food chemicals to build up a level of resistance by regular exposure to small amounts in a controlled way, but care must be taken, the aim being to build up a varied diet with adequate composition.

Prognosis

The prognosis of children diagnosed with intolerance to milk is good: patients respond to diet which excludes cow's milk protein and the majority of patients succeed in forming tolerance.^[58] Children with non-IgE-mediated cows milk intolerance have a good prognosis, whereas children with IgE-mediated cows milk allergy in early childhood have a significantly increased risk for persistent allergy, development of other food allergies, asthma and rhinoconjunctivitis.

A study has demonstrated that identifying and appropriately addressing food sensitivity in IBS patients not previously responding to standard therapy results in a sustained clinical improvement and increased overall well being and quality of life.

Drug intolerance or drug sensitivity is a lower threshold to the normal pharmacologic action of a drug. It is not to be confused with drug allergy. Drug intolerance is uncommon and idiopathic, thus extremely difficult to predict except in persons with a prior history or a family history of intolerance to that specific drug. Some drug intolerances are known to result from genetic variants of drug metabolism

The following position paper focuses primarily on the approach when pseudoallergic reactions to food ingredients are suspected in chronic urticaria. In this disease pseudoallergy is often suspected as a trigger factor. As no results from large controlled studies in the sense of evidence-based medicine exist, nonstandardized and often time-consuming diagnostic procedures are performed on an individual basis. The present guideline proposes a simplified approach that has become established in several institutions. Primarily practical reasons employing this scheme, as controlled clinical studies supporting the approach are not available. Statements on the frequency of relevant pseudoallergic reactions to food ingredients are rare. Provocation with additives that have long been viewed as major causes leads to pseudoallergic reactions only in a minority of patients whose symptoms improve during an elimination diet. Even a pseudoallergen -rich challenge diet (see below), that includes natural foods in addition to addi tives as triggers, elicits symptoms only in a proportion of responders to diet. This observation suggests healing may be initiated by a diet that avoids known triggers for a limited period of time. The justification for a low-pseudoallergen diet is supported by observations in patients with chronic urticaria; especially patients

with increased gastroduodenal permeability profit from the diet. The permeability

of the gastric mucosa normalizes in patients who profit from the diet over 3-4 weeks.

Pseudoallergic reactions are elicited by additives but also by natural food ingredients.

The list of pseudoallergens used diagnostically in clinical practice is to an extent based on case reports of documented hypersensitivity reactions. Since the spectrum of additives has changed considerably in recent years, clinically relevant food components may be missing in common diagnostic protocols or irrelevant additives may still be tested. Because of these uncertainties, the evaluation of the clinical relevance of pseudoallergens requires a uniform and regularly updated approach for investigating reactions to food ingredients. In the following guideline of the Task Force on Food Allergy of DGAKI

(German Society of Allergology and Clinical Immunology, Deutsche Gesellschaft fur Allergologie und klinische Immunologie) and the above mentioned institutions, the diagnostic guidelines for suspected pseudoallergy are updated, and will be regularly re-evaluated with respect to the spectrum of pseudoallergens

Role of in vitro and in vivo tests

In contrast to IgE-mediated reactions to food, where in vitro tests and skin tests have an established role in diagnostics before oral provocation tests are performed, no reliable laboratory or  skin tests are available for pseudoallergic reactions at this time.

The proportion of patients with altered histamine metabolism appears elevated in the diseases described above. These observations might explain why a diet poor in biogenic amines helps some patients. Skin tests (rub tests, prick tests, perhaps intracutaneous tests) can indicate an IgE-mediated reaction. Such reactions are extremely rare, e. g. to.

With a history of threatening symptoms (i. e. severe airway obstruction, severe angioedema, anaphylactic reactions) skin tests should be considered for the sake of safety. They usually are negative in the case of pseudoallergic reactions and are thus not of aid in diagnostics in a strict sense, so that identification of possible triggers always demands an elimination diet and oral challenge.

There are no reliable skin or laboratory tests as objective diagnostic parameters.

In principle, targeted testing of one or few ingredients when specific suspicion of an intolerance e. g. tartrazine intolerance in association with an already known intolerance to acetylsalicylic acid (idiosyncrasy) or targeted provocation following a positive skin test must be differentiated from an untargeted search in the face of chronic complaints (usually chronic urticaria or chronic recurrent angioedema) which is covered first in the following text.

Elimination diets for chronic urticaria and recurrent angioedema

Acute urticaria (i. e. signs and symptoms < 6 weeks) or a short episode of angioedema does not constitute an indication for extensive diagnostic efforts. With chronic urticaria or angioedema recurring in a time period longer than 6 weeks, other causes or trigger factors should be excluded by the diagnostic approach summarized in the DDG Guideline Urticaria (Zuberbier et al., 2003) or in the European EAACI/GA2LEN/EDF guidelines (Zuberbier et al., 2006a and b). Physical urticaria including urticaria factitia, immediate-type allergies and infectious triggers should be excluded. Acute urticaria or a short episode of angioedema does not constitute an indication for an expensive and time-consuming diagnostic approach. If the basic diagnostic evaluation of chronic urticaria is negative, a low-pseudoallergen diet can be considered.

If no infectious cause is identified, a lowpseudoallergen diet four at least four weeks is recommended. If no improvement of symptoms occurs, perhaps a stricter oligoallergenic basic diet (compare Table 3) over further 5 to 7 days, as recommended for IgE-mediated reactions, should be followed . Further, in individual cases symptom-oriented special tests at specialized centers (including hypoallergenic liquid diet might be necessary.

Here it is stated that “an elimination diet consisting of unprocessed self-prepared food is a cost-effective diagnostic tool to rule out natural pseudoallergens and food additives as cause or trigger factors in chronic urticaria…For the duration of four weeks no nutritional deficiencies must be feared as the low-pseudoallergen diet contains all macro- and micronutrients in sufficient amounts, as long as the missing fruits are compensated by a significantly higher consumption of vegetables”.

In severe cases a potato-rice diet can be followed for a limited time period of several days. In chronic urticaria possible success with diet usually can only be expected after a longer period of time, i. e. one to three weeks. A short-term potatorice diet does not harm an otherwise healthy person, but a week-long diet lowers compliance significantly.

With outpatient diets, the danger of dietary errors is large. Ideally, but not always possible in day-to-day practice, detailed counseling by a nutritional expert should be performed. In any case, the foods eaten should be noted by the patient daily in a food diary. As far as possible, suppression of symptoms with drugs should be avoided during the diet.

In order to increase the patient’s compliance, one can consider antihistamines for the first 10–14 days, when no improvement due to the diet can be expected.

After this the drugs should be discontinued in order to evaluate the response to the diet. During the diet the severity of chronic urticaria should be assessed with an urticaria score daily (usually by the patient) and documented in a diary. The urticaria score takes into account an objective (number of wheals) and a subjective (evaluation of pruritus) parameter. Angioedema is similarly evaluated (score from 0–3). The low-pseudoallergen diet leads to an improvement of symptoms with regard to pruritus and extent of wheals in many patients with urticaria. If no improvement of clinical symptoms occurs under this regimen and perhaps an oligoallergenic diet over 5 to 7 days, triggering of symptoms by food is improbable and provocation tests are not sensible.

Oral provocation without indication of specific causes

If there is a significant improvement or complete remission of symptoms (total score 0) during the low-pseudoallergen diet, inpatient admission for the sake of safety for oral challenge testing should occur. There should be no angioedema at the time point of provocation. Drugs that could influence the provocation such as antihistamines and corticosteroids should be discontinued sufficiently long before testing (i. e. 1 week for antihistamines, 3 weeks for systemic steroids).

Provocation should first be performed in form of a pseudoallergen-rich challenge diet under observation with the availability of emergency medical care. If no reaction occurs after one day a second day of a pseudoallergen-rich challenge diet is recommended due to the possibility of a dose-dependent effect (Table 4). Table 5 is an example of such a “super meal” which is high on additives as well as biogenic amines and natural aromas. This provocation diet can be employed as a “search test”. Of course, individual foods can be replaced by other additive-rich foods. This is particularly necessary when an IgE-mediated allergy towards a food is already known. The pseudoallergen-rich provocation test is not free of allergens! The patient should give informed consent after being informed about the nature of the testing and the likelihood of gaining information. Correct planning and execution of the testing is the physician’s responsibility.

Beware: Oral challenge tests with pseudoallergens can cause systemic reactions and require close observation over a time period of 16 to 24 hours.

If the nutritional history shows that the diet of the patient contains no or only certain additives, an individual provocation adapted to the particular patient is desirable. This should then be limited to the natural foods as triggers and only suspected additives should be tested in a targeted fashion. When clinical reactions fail to occur, extension of the challenge with the pseudoallergen-rich provocation diet for further 2 days is recommended. After positive reactions, characterized by objective symptoms such as urticaria and angioedema, symptomatic therapy should be followed by a renewed diet phase until improvement is observed. To rule out additives as trigger of the observed reactions, a subsequent collective group exposition with additives listed in Table 4 is suggested. This list must continually be updated as to new, but also as to no longer or not relevant triggers. When collective exposition leads to a positive reaction, step-by-step exposition of individual components follows. In case of severe past reactions (e. g. urticaria with extensive angioedema) a titrated  provocation of individual components instead of collective exposition is recommended (see below).

When in addition to or independent of urticaria or angioedema other signs or symptoms occur (respiratory, anaphylactoid symptoms) further provocation tests should be performed with defined pseudoallergens in incremental dosages with the availability of emergency care.

When adverse reactions against histamine are suspected, challenge with histamine dihydrochloride (0.75 mg/kg body weight and 1.5 mg/kg body weight) (Fiedler et al., 2005) – after exclusion of medical contraindications and with availability of emergency care – can be considered.

Glutamate (4 g) can also be employed in an isolated manner when indicated.

If a positive reaction occurs only to the pseudoallergen-rich provocation test, a slow build-up of the diet is performed, where every three days a formerly prohibited food is added, until ideally an individual “therapeutic diet” can be recommended.

The proposed pseudoallergen-rich challenge diet is designed to reflect the day-to-day situation of the patient better than the provocation with individual substances. Nevertheless, only rarely are clinically reactions (urticaria) observed in patients whose chronic urticaria had previously improved under a low-pseudoallergen diet. By means of the uniform approach further focusing on previously unsuspected pseudoallergens, e. g. fragrances.

Oral provocation with individual components

For reactions to collective group exposition, for severe clinical reactions or for the relatively rare clinical suspicion of a defined pseudoallergen as trigger of clinical symptoms (e. g. sulfites in causing respiratory tract obstruction) a doubleblind oral provocation with individual substances is suggested. For severe clinical reactions, in departure from the above mentioned dosages, a titrated exposition to defined substances is recommended.

Due to the possibility of delayed onset of symptoms, in most cases only one substance group should be provoked per day.

With known bronchial asthma or anaphylactoid reactions, slow increase in l dosage is an absolute necessity.

Fundamental issues in oral provocation

For double-blind oral provocation the same rules as recently published for IgE-mediated reactions apply. The ratio verum: placebo should ideally be 1:1. For reasons of practicability and based on the low frequency of objective reactions in patients who are not overly fearful, a ratio of 4:1 can be justified.

Clinical evaluation should be done by the physician, at least for an entire provocation block. In the evaluation of reactions subjective and objective symptoms should be differentiated on a standardized documentation sheet. The evaluating physician must before each following step state in writing if the previous clinical reaction is to be judged positive or negative. De-blinding occurs only after completion of the planned challenge protocol.

A positive placebo reaction draws possible positive verum challenges into question. In such cases the previous tests must be repeated and more placebo challenges be planned. In patients with exercise-dependent pseudoallergic reactions, oral provocation should be followed by adequate exercise (e. g. treadmill) after 45 to 60 minutes.

Approach for extracutaneous symptoms

Pseudoallergic reactions that do not present as urticaria and/or angioedema are – with the exception of intolerance of analgesic drugs – not as well studied and possibly rarer, too. Reactions can occur in the upper respiratory tract (rhinitis, laryngeal edema), the lower airways (asthma), as well as lead to gastrointestinal symptoms and circulatory disorders including shock. The approach with regard to drug-free intervals is identical to that for urticaria.

In asthma with sulfite intolerance, direct SO2contact with the mucous membranes is apparently of importance and administration in capsule form can lead to false-negative results. Provocation with a soda beverage whose acid pH promotes SO2 release (0.1 mg/ml) is better. Inhalation tests are also possible (Metcalfe et al., 1996). Both should only be performed if emergency medical care is available, as threatening reactions are possible.

For respiratory reactions regular peak flow measurements (supplemented by pulmonary function tests) are sensible.

When dealing with gastrointestinal complaints which are often not objective, double-blind conditions – as far as possible – are of special significance. For circulatory reactions control is by regular or continual blood pressure and pulse monitoring in a supine position. For challenges in signs and symptoms of the respiratory tract inhalation provocation should be considere

The terms “drug allergy,” “drug hypersensitivity,” and “drug reaction” are often used interchangeably. Drug reactions encompass all adverse events related to drug administration, regardless of etiology. Drug hypersensitivity is defined as an immune-mediated response to a drug agent in a sensitized patient. Drug allergy is restricted specifically to a reaction mediated by IgE.

Drug reactions can be classified into immunologic and nonimmunologic etiologies (Table 1). The majority (75 to 80 percent) of adverse drug reactions are caused by predictable, nonimmunologic effects.1 The remaining 20 to 25 percent of adverse drug events are caused by unpredictable effects that may or may not be immune mediated.1 Immune-mediated reactions account for 5 to 10 percent of all drug reactions and constitute true drug hypersensitivity, with IgE-mediated drug allergies falling into this category.

TABLE 1 Immunologic and Nonimmunologic Drug Reactions

The Gell and Coombs classification system describes the predominant immune mechanisms that lead to clinical symptoms of drug hypersensitivity (Table 2). This classification system includes: Type I reactions (IgE-mediated); Type II reactions (cytotoxic); Type III reactions (immune complex); and Type IV reactions (delayed, cell-mediated). However, some drug hypersensitivity reactions are difficult to classify because of a lack of evidence supporting a predominant immunologic mechanism. These include certain cutaneous drug reactions (i.e., maculopapular rashes, erythroderma, exfoliative dermatitis, and fixed drug reactions)4,5  and specific drug hypersensitivity syndromes (Table 3).

Gell and Coombs Classification of Drug Hypersensitivity Reactions

MHC = major histocompatibility complex.

*—Suspected Type IV reaction, mechanism not fully elucidated.

TABLE 3
Specific Drug Hypersensitivity Syndromes Caused by Non-IgE Immune Mechanisms

Unpredictable, nonimmune drug reactions can be classified as pseudoallergic, idiosyncratic, or intolerance. Pseudoallergic reactions are the result of direct mast cell activation and degranulation by drugs such as opiates, vancomycin (Vancocin), and radiocontrast media. These reactions may be clinically indistinguishable from Type I hypersensitivity, but do not involve drug-specific IgE. Idiosyncratic reactions are qualitatively aberrant reactions that cannot be explained by the known pharmacologic action of the drug and occur only in a small percent of the population. A classic example of an idiosyncratic reaction is drug-induced hemolysis in persons with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Drug intolerance is defined as a lower threshold to the normal pharmacologic action of a drug, such as tinnitus after a single average dose of aspirin.

Epidemiology

Adverse drug reactions caused by immune and nonimmune mechanisms are a major cause of morbidity and mortality worldwide. They are the most common iatrogenic illness, complicating 5 to 15 percent of therapeutic drug courses.8,9 In the United States, more than 100,000 deaths are attributed annually to serious adverse drug reactions.10 Three to 6 percent of all hospital admissions are because of adverse drug reactions, and 6 to 15 percent of hospitalized patients (2.2 million persons in the United States in 1994) experience a serious adverse drug reaction.8–11 Epidemiologic data support the existence of specific factors that increase the risk of general adverse drug reactions, such as female gender,12 or infection with human immunodeficiency virus (HIV),13 or herpes14  (Table 4).12–16 Factors associated with an increased risk for hypersensitivity drug reactions include asthma,15 systemic lupus erythematosus,16 or use of beta blockers15  (Table 4).12–16 Although atopic patients do not have a higher rate of sensitization to drugs, they are at increased risk for serious allergic reactions.17

TABLE 4
Patient Risk Factors for Adverse Drug Reactions

HIV = human immunodeficiency virus.

Clinical Manifestations

True hypersensitivity adverse drug reactions are great imitators of disease and may present with involvement of any organ system, including systemic reactions such as anaphylaxis. Drug reactions commonly manifest with dermatologic symptoms caused by the metabolic and immunologic activity of the skin. The most common dermatologic manifestation of drug reaction is morbilliform rashes. Typically, an erythematous, maculopapular rash appears within one to three weeks after drug exposure, originates on the trunk, and eventually spreads to the limbs. Urticaria is typically a manifestation of a truly allergic, Type I reaction, but it may appear with Type III or pseudoallergic reactions as well. Severe nonallergic, hypersensitivity cutaneous reactions (i.e., erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis) represent bullous skin diseases that require prompt recognition because of their association with significant morbidity and mortality. Eczematous rashes are most commonly associated with topical medications and usually represent contact dermatitis, which is classified as Type IV reaction to a drug exposure.

Clinical Evaluation

Drug hypersensitivity reactions not only should be included in the differential diagnosis for patients who have the typical allergic symptoms of anaphylaxis, urticaria, and asthma, but also for those with serum sickness-like symptoms, skin rash, fever, pulmonary infiltrates with eosinophilia, hepatitis, acute interstitial nephritis, and lupus-like syndromes. A diagnosis of drug hypersensitivity depends on identifying symptoms and physical findings that are compatible with an immune drug reaction (Figure 11).

Evaluation and Management of Drug Reaction

Algorithm for the evaluation and management of drug reaction.

*--Not for Stevens-Johnson syndrome/toxic epidermal necrolysis.

Adapted with permission from Executive summary of disease management of drug hypersensitivity: a practice parameter. Joint Task Force on Practice Parameters, the American Academy of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 1999;83:668.

The initial history should include a recording of all prescription and nonprescription drugs taken within the last month, including dates of administration and dosage. The temporal relationship between drug intake and the onset of clinical symptoms is critical. Unless the patient has been previously sensitized to a drug, the interval between initiation of therapy and the onset of reaction is rarely less than one week or more than one month. Patients should be asked about previous drug exposures and reactions.

The physical examination may provide further information to support drug hypersensitivity. A prudent initial step is an evaluation for signs and symptoms of an immediate generalized reaction, because this is the most severe life-threatening form of an adverse drug reaction. Warning signs of impending cardiovascular collapse include urticaria, laryngeal or upper airway edema, wheezing, and hypotension. Signs suggestive of serious adverse drug reactions include the presence of fever, mucous membrane lesions, lymphadenopathy, joint tenderness and swelling, or an abnormal pulmonary examination. A detailed skin examination is essential, because the skin is the organ most frequently and prominently affected by adverse drug reactions. Distinguishing between the various types of skin lesions is important, because this may provide substantial clues to the possible immune-mediated mechanism of the drug reaction (Table 5).

Cutaneous Symptoms of Drug Hypersensitivity Reactions

Laboratory Evaluation

The goal of diagnostic testing is to evaluate biochemical or immunologic markers that confirm activation of a particular immunopathologic pathway to explain the suspected adverse drug effect. Laboratory evaluation is guided by the suspected pathologic mechanism (Table 6)18.

Diagnostic Testing and Therapy for Drug Hypersensitivity

RAST = radioallergosorbent test; ESR = erythrocyte sedimentation rate; NSAIDs = nonsteroidal anti-inflammatory drugs.

*—This is an investigational test.

Suggested Patch Testing Procedures for Drug-Induced Contact Dermatitis

Diagnosis

The diagnosis of drug hypersensitivity is usually based on clinical judgment, because definitive, confirmatory drug-specific testing is often difficult. Table 8 outlines the general criteria for the diagnosis of drug hypersensitivity reactions.

General Criteria for Drug Hypersensitivity Reactions

Once the diagnosis has been established, appropriate documentation should be included in the medical record specifying the causative drug and the nature of the adverse effect. Immune-mediated drug hypersensitivity reactions typically pose a predictable, more serious health risk with re-exposure to a drug. Nonimmune drug reactions tend to be less severe and less reproducible. The continued use of an offending drug may be appropriate if the risk of not treating the underlying disease is greater than the risk of continuing the drug, and if no suitable alternative exists. In these cases, it is essential that the patient be closely monitored by an experienced physician. When discontinuing a drug, the patient should be provided with a list of substitute medications for future use.

Therapy and Management

The most important and effective therapeutic measure in managing drug hypersensitivity reactions is the discontinuation of the offending medication, if possible. Alternative medications with unrelated chemical structures should be substituted when available. The clinical consequences of medication cessation or substitution should be closely monitored. In the majority of patients, symptoms will resolve within two weeks if the diagnosis of drug hypersensitivity is correct.

Additional therapy for drug hypersensitivity reactions is largely supportive and symptomatic (Table 6). Systemic corticosteroids may speed recovery in severe cases of drug hypersensitivity. Topical corticosteroids and oral antihistamines may improve dermatologic symptoms. The severe drug reactions of Stevens-Johnson syndrome and toxic epidermal necrolysis require additional intensive therapy.29

Analgesic intolerance

Intolerance to analgesics, particularly NSAIDs, is relatively common. Its cause is believed to be variation in the metabolism of arachidonic acid. Symptoms include chronic rhinosinusitis with nasal polyps, asthma, gastrointestinal ulcers, angioedema, and urticaria. NSAIDs can cause several allergic and "pseudoallergic" reactions. Allergic reactions are immunologic reactions to NSAIDs that are presumed IgE-mediated. Pseudoallergic reactions are non-immunologic.

Allergic and "pseudoallergic" reactions to NSAIDs

Pseudoallergic reactions are non-immunologic abd are related to the COX-1 inhibition. They can be elicited by any NSAID that inhibits C OX-1, including aspirin. Precise mechanism has not been established. A

Pseudoallergic reactions are divided into 4 types:
- Type 1: NSAID-induced asthma and rhinosinusitis
- Type 2: NSAID-induced urticaria/angioedema in patients with chronic urticaria
- Type 3: NSAID-induced urticaria/angioedema in otherwise asymptomatic individuals
- Type 4: Blended reactions in otherwise asymptomatic individuals
Diagnosis
There are no in vitro or skin testing methods available. Definitive diagnosis requires a challenge procedure, although this is only indicated if the patient has a specific need for regular NSAID therapy (ie, usually NSAIDs for rheumatologic disease or aspirin for cardiovascular disease).
Management of pseudoallergic reactions
Challenge procedures
If a definitive diagnosis is required, then a provocative challenge procedure must be performed.
Without additional information, the clinician must advise the patient to avoid all NSAIDs. However, a challenge procedure with aspirin would clarify whether the patient reacts to all COX-1 inhibitors (pseudoallergic), or only to ibuprofen (allergic).

Alternative to the challenge

An alternative to the challenge is to administer a highly selective COX-2 inhibitor. Highly selective COX-2 inhibitors (eg, celecoxib) are tolerated by patients with pseudoallergic reactions. These agents demonstrate at least a 200 to 300-fold selectivity for inhibition of COX-2 over COX-1 at the defined therapeutic doses.
It is generally safe for patient with a pseudoallergic NSAID reaction to take a highly selective COX-2 inhibitor, such as celecoxib. Some allergists prefer to give an initial dose in a medically supervised setting (eg, a clinic), although there are no reported cases of pseudoallergic reactions who subsequently reacted to celecoxib.
Management of allergic reactions
Type 5 and 6 reactions are presumed IgE-mediated reactions to single NSAIDs. Patients with these types of reactions should avoid the causative agent.
Patients with types 5 and 6 reactions may require diagnostic challenge with aspirin to confirm that they are not sensitive to all COX-1 inhibitors (ie, exclude pseudoallergy), if the history is not sufficient to determine this. Confirmed cases of anaphylaxis to aspirin have not been reported.
Patients with types 5 or 6 reactions may safely take NSAIDS that are structurally dissimilar to the drug that caused the initial reaction.
However, selective COX-2 inhibitors may be unsafe in subjects with urticaria and/or angioedema caused by hypersensitivity reactions to NSAIDs with cross-intolerance if they are intolerant to paracetamol. 

II type of the reactions of hypersensitivity

The second type of the reaction is characterized by the reaction of the antibody with the antigen on the surface of the host cell, which causes the destruction of this cell.

There may be simple chemical substances, components of the cellular membrane, the noncellular structures. The condition of development is excess of the antigen, which is attached to the cells (for example, to the erythrocytes). Shock cells - most frequently they are cells of the blood, endothelium of the vessels, hepatocytes, epithelium of the kidneys. When the allergen is attached to the cells, their surface becomes antigenically foreign, resulting in humoral immune response, immunoglobulins G are synthesized, cells are destroyed, and the allergen disappears. This phenomenon was called the antibody- dependant cytotoxicity.

Example: analgin- induced agranulocytosis. In some people the introduction of analgin leads to the fixation of its molecules on the cellular membrane of the precursor cells of leukocytes. This causes change in the structure of the cellular membrane and formation of the complex antigen, which becomes foreign for the organism and habitual immune response develops to it with the formation of the antibodies related to IgG. The antibodies bind with the antigen with the formation of the immune complex, which leads to the activation of the complement system, phagocytosis, antibody- dependant cytotoxicity is induced, and finally the process comes to the end with the destruction of the target cell.

The specific antibody, usually IgG or IgM, synthesized against the antigen, interacts with it on the surface of the cell and causes damage of the cell in several ways:

1) Lysis of the cell - the activation of the cascade of the complement results in formation of “membrane attacking” complex of C5b6789, which causes lysis of the cell membrane.

2) Phagocytosis - the cell carrying antigen is absorbed by the phagocytizing macrophages, lymphocyte - killers, cytotoxic lymphocytes, which have Fc or C3b receptors; it allows them to recognize complexes the antigen-antibody on the cell.

The manifestations of the reaction of II type hypersensitivity depend on the type of the cell, which carries antigen.

Figure II.3. Immune malfunctions leading to tissue damage: type II—antibody-dependent cytotoxic hypersensitivity. Antibodies bind to antigenic determinants on cells, inducing activation of complement, phagocytic cells, or cytotoxic cells, leading to cell lysis (Klaus D. Elgert, Immunology, 1996).

 

Cytotoxic type: medicinal allergy, immune leucopenia; the hemolytic disease of newborns with the rhesus – conflict, the autoimmune hemolytic anemia and thrombcytopenia, Goodpasture’s syndrome, chronic active hepatitis, ulcerous colitis, Sjogren's syndrome, myasthenia, pemphigus, some cases of juvenile diabetes mellitus and other diseases.

Reactions with destruction of the erythrocytes. The posthemotransfusion reactions - the antibodies in the patient’s serum react with the antigens on the transfused red cells, causing either indirect complement intravascular hemolysis, extended hemolysis as a result of immune phagocytosis by the spleen macrophages. There are a large number of erythrocyte antigens, which can cause hemolytic reactions during transfusions (ABO, Rh, Kell, Kidd, Lewis, etc). Hemolysis may develop during the repeated transfusion of Rh+ blood Rh- patient.

The hemolytic disease of newborns develops in penetration of the maternal antibodies through the placenta, which manifest their activity against the antigens of the erythrocytes of the fetus (Rh and ABO) and destroy them. The hemolytic disease of newborns is more frequently observed with the Rh- incompatibility, as anti- Rh of the antibodies in the mother’s plasma usually are IgG, which easily penetrate through the placenta. IgM is usually anti-A and anti-B antibodies, which cannot penetrate through the placenta in the normal conditions.

Other hemolytic reactions - hemolysis may be caused by the medicines, which act as haptens in combination with the proteins of the erythrocyte membrane or it may develop in the infectious diseases, associated with development of antierythrocyte antibodies, for example, in infectious mononucleosis, mycoplasmal pneumonia.

Reactions with destruction of the neutrophils - maternal antibodies to the antigens of the fetus, neutrophils may cause neonatal leucopenia, if they penetrate through the placenta. Sometimes the posttransfusion reactions arise because of the activity of the host serum against the leukocyte HLA of the donor’s antigens.

Reactions with destruction of the thrombocytes - the posttransfusion feverish reactions and neonatal thrombocytopenia can arise as a result of the factors, described above for the leukocytes. Idiopathic thrombocytopenic purpura is a frequent autoimmune disease, in which the antibodies are formed against their own antigens of the thrombocyte membrane.

Reactions on the basal membrane- antibodies against the antigens of the basal membranes in the renal glomerules and the pulmonary alveoli develop in the Goodpasture’s syndrome.

Inhibition - the inhibiting antibodies play a key role in severe myasthenia (myasthenia gravis) - the disease, which is characterized by the disturbance of the neuromuscular transmission and development of muscular weakness. The disease is caused by the antibodies (IgG), directed at the acetylcholine receptors on the motor endplate. Antibodies compete with the acetylcholine for the place of binding on the receptor, thus blocking the transmission of the nerve impulse. The mechanism of inhibition is also the basis of the pernicious anemia, in which the antibodies bind with the internal factor, and they inhibit the absorption of the vitamin B₁₂.

Goodpasture’s syndrome is an autoimmune disease that can damage the lungs and kidneys. Why this happens is not fully understood. Researchers have identified a number of possible causes, among them the presence of an inherited component: exposure to certain chemicals, including hydrocarbon solvents and viral infections. First signs may be vague, such as fatigue, nausea, difficulty breathing, or paleness. These signs are followed by kidney involvement, represented first by small amounts of blood in the urine, protein in the urine, and other clinical and laboratory findings. Goodpasture’s syndrome may last only a few weeks or as long as 2 years. Bleeding in the lungs can be very serious and even fatal in some cases. But Goodpasture’s syndrome does not usually lead to permanent lung damage. Damage to the kidneys, however, may be long-lasting. To diagnose Goodpasture’s syndrome use a blood test, but a kidney or lung biopsy may be necessary to check for the presence of the harmful antibodies. Goodpasture’s syndrome is treated with oral immunosuppressive drugs—cyclophosphamide and corticosteroids, plasmapheresis.

Sjogren's syndrome is a chronic, slowly progressive, inflammatory autoimmune disorder characterized by the infiltration of specialized cells of the immune system called lymphocytes (T-cells in the majority of cases), monocytes, and plasma cells into the parotid (salivary) glands and lacrimal (tear) glands. Two distinct forms of Sjogren's syndrome have been recognized: Primary Sjogren's syndrome - defined as dry eye and dry mouth that occurs by itself and is not associated with another autoimmune disorder. Secondary Sjogren's syndrome - characterized by dry eye and dry mouth that occurs in the presence of a major underlying autoimmune connective tissue disease such as rheumatoid arthritis, systemic lupus erythematosus, or scleroderma. The classic symptoms of Sjogren's syndrome affecting the oral cavity and the eyes. The systemic or extraglandular symptoms of Sjogren's: sinus symptoms; cutaneous (skin) symptoms; vasculitis; pulmonary symptoms; kidney/bladder symptoms; gastrointestinal symptoms; neurological symptoms; gynecological symptoms. How Sjogren's syndrome is diagnosed based on factors such as symptoms, patient history, physical examination, and examination of the oral cavity and eyes. Special laboratory tests that are used to confirm the diagnosis of Sjogren's syndrome that are designed to measure abnormalities in the production of saliva and tears. Currently there is no known cure for Sjogren's syndrome. The major goals of treatment are to control the symptoms and prevent or limit the involvement of other organs of the body. The treatment that to better manage the symptoms associated with dry mouth: saliva substitutes; saliva stimulants; interferon-alpha; good oral hygiene practices. The treatment that to better manage dry eye symptoms: artificial tears; methylcellulose inserts; eye ointments; muscarinic agonist drugs; immunomodulatory drugs; autologous serum drops; punctual occlusion surgery. The treatment manifest systemic or extraglandular symptoms of other body organs such as the skin, lungs, kidney, gastrointestinal tract, or vagina.

IV type of hypersensitivity - delayed- type hypersensitivity (DTH)

The fourth type of the reaction is the reaction of the cell-dependent type of hypersensitivity (the cellular reaction or hypersensitivity of the retarded type). The reaction caused by macrophages and Th1- lymphocytes, which answer for the stimulation of the cellular immunity. It develops mainly in 1-3 days after the effect of the allergen: there is consolidation and inflammation of the tissue, resulting in its infiltration by T-lymphocytes and macrophages. Any organs and tissues may be involved in the process. Skin, gastrointestinal tract, respiratory organs are more frequent affected in development of the fourth type allergic reactions.

Figure II.6. Immune malfunctions leading to tissue damage: type IV—cell-mediated (delayed-type) hypersensitivity. Following secondary exposure to the same antigen, this tissue damage is mediated by antigen-sensitized T cells through release of cytokines. The cytokines attract and activate macrophages that release mediators, leading to inflammatory reactions (Klaus D. Elgert, Immunology, 1996).

 Three examples of Type IV reaction:

Contact hypersensitivity is characterized by a reaction at the site of contact with the allergen. It is an epidermal response most often elicited by small molecules called haptens. The cell involved in antigen presentation at this site is the Langerhans cell. The pathway from initial exposure involves sensitization (with Langerhans cells presenting allergen to CD4+ helper T-cells) and exposure, followed by aggregation of mononuclear cells around blood vessels and glands in the epidermis and edema. A variety of cytokines are involved in this process, including IL-2, IL-3, IFN and GM-CSF. The reaction decreases 48-72 hours following exposure.

Tuberculin hypersensitivity was first observed when soluble antigens from organisms such as mycobacteria were administered subcutaneously. In these individuals fever, general unwellness, plus an area of red, hard swelling was observed. The skin test for Tuberculosis is of this nature. This reaction is induced by a series of cellular migrations and activations: T-cell migration from capillaries; disruption of collagen in dermis; macrophage infiltration; lymphocytes and macrophages express HLA-DR; granulomatous appearance, no edema, self-limiting.

Granulomatous hypersensitivity is characterized by persistence of the antigen within macrophages as well as of the lesion. Such antigens are particulate matter such as talc and silica but also mycobacteria. The characteristic cells found in the lesion are epitheloid cells (probably macrophages) and giant-cells (multi-nucleated macrophages). The granuloma consists of a hard core of cells sometimes with a necrotic core. This is surrounded by lymphocytes with a deposition of collagen fibres.

 

Figure II.7. The hapten forms a hapten-carrier complex in the epidermia. Langerhans' cells internalize the antigen, undergo maturation, and migrate via afferent lymphatics to the paracortical area of the regional lymph node where peptide/MHC complexes on the surface of the Langerhans' cell can also be directly haptenated. As interdigitating cells, they present antigen to CD4⁺ T cells (I.Roitt et al., Immunology, 2001).

 

Delayed-type hypersensitivity is the basis of the following allergic reactions: contact dermatitis; brucellosis; infectious-allergic rhinitis; rejection reaction of the transplant and others.

The most important diseases with the granulomatous reactions of the delayed - type hypersensitivity are leprosy, tuberculosis, shistosomosis, sarcoidosis, Crohn disease.

Form of  delayed-type hypersensitivity

 

Infectious diseases (brucellosis, glanders, tularemia, tuberculosis, leprosy, toxoplasmosis, many mycoses and others) are accompanied by development of DTH; therefore skin-allergic tests with the allergens of causative agents are used in diagnostics (by tuberculins, brucellin, malleinom, tularin, toxoplasmin and others).

Mechanisms: chemotaxis is the directed migration of the cells in response to the production of the specific chemotaxic factors; inhibition of macrophages - macrophages (phagocytizing cells) lose mobility and cannot leave the zone of reaction; the activation of phagocytes - activation of the cells, which are specialized in the absorption of the cellular material of endogenous and exogenous origin. The blastogenic effect is the stimulation of proliferation and differentiation of the organism cells. Delayed-type hypersensitivity is the immune response, which develops in 48 - 72 hours after contact with the antigen

Tuberculin test is the prototype of this form of response.

 

Figure II.8. The stages of a delayed-type hypersensitivity reaction. The first phase involves uptake, processing, and presentation of the antigen by local antigen-presenting cells. In the second phase. T_H1 cells that were primed by a previous exposure to the antigen migrate into the site of injection and become activated. Because these specific cells are rare, and because there is no inflammation to attract cells into the site, it can take several hours for a T cell of the correct specificity to arrive. These cells release mediators that activate local endothelial cells, recruiting an inflammatory cell infiltrate dominated by macrophages and causing the accumu­lation of fluid and protein. At this point, the lesion becomes apparent (Charles A. Janeway et al., Immunobiology, 1999).

 

The fifth type of hypersensitivity of the reaction stimulating type

Five types of allergic reactions (or the reactions of hypersensitivity) are distinguished today.

The fifth type of the reaction is a reaction of hypersensitivity, in which the antibodies exert the stimulating influence on the function of cells. The example of this reaction is thyrotoxicosis related to the autoimmune diseases, in which the overproduction of thyroxin occurs due to the activity of specific antibodies. ABs participate in the process in this type, directed at the different components of the cellular surface, for example, the receptors of the physiological mediators (acetylcholine, adrenoreceptors, receptors for the hormones, etc). AB in the 5th type of the allergic reactions is more frequently related to the immunoglobulins of the class IgG. Bronchial asthma, diabetes mellitus, autoimmune diseases of the endocrine glands and others may have a course of the 5th type.

 

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3.    Roderick Nairn, Matthew Helbert.  Immunology for medical students / / Hardboun. – 2012. –326 p.

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5.    Dédée Murrell. Autoimmune Diseases of the Skin, An Issue of Immunology and Allergy Clinics.-  Imprint: Saunders.- Published: May 2012