Atopic and allergic conditions: causes, symptoms, diagnosis, treatment

Type I hypersensitivity reactions include atopic and many allergic disorders. The terms "atopy" and "allergy" are often used as synonyms, but in fact they are different concepts. Atopy is an excessive IgE-mediated immune response; all atopic disorders are type I hypersensitivity reactions. Allergy is any excessive immune response to an external antigen, regardless of the mechanism. Thus, any atopy is based on an allergic reaction, but many allergic reactions (for example, hypersensitivity pneumonitis) are not atopic disorders. Allergic diseases are the most common diseases in humans.

Atopy most commonly affects the nose, eyes, skin, and lungs. These disorders include atopic dermatitis, contact dermatitis, urticaria, and angioedema (which may present primarily with skin lesions or symptoms of systemic disease), latex allergy, allergic lung disease (eg, asthma, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis), and allergic reactions to stinging insects.

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Causes of atopic conditions

The development of allergy is caused by a complex of genetic, environmental and local factors. The role of genetic factors is the presence of a hereditary predisposition to diseases associated with atopy and specific HLA loci, and polymorphism of genes responsible for high affinity, the TNF chain of the IgE receptor, IL-4nCD14.

Environmental factors interact with genetic factors to maintain the Th2 immune response, which activates eosinophils and IgE production and is proallergic. Normally, initial exposure to bacterial and viral infections and endotoxins (lipopolysaccharides) in early childhood shifts the response from natural Th2 to TM, which suppress Th2 and induce tolerance to foreign antigens; this mechanism may be mediated by Toll-like receptor-4 and is realized through the development of a population of regulatory T lymphocytes (CD4+, CD25+), which suppress the Th2 response. Currently, in developed countries, there is a trend towards small families with a small number of children, a cleaner home environment, early use of vaccination and antibiotic therapy, which deprives children of such exposure to antigens and suppresses Th2 suppression; such behavioral changes may explain the widespread prevalence of some allergic conditions. Other factors that contribute to the spread of allergic conditions include chronic contact with the allergen and sensitization, diet, and physical activity.

Local factors include adhesion molecules of the epithelium of the bronchi, skin, and gastrointestinal tract, which direct Th2 to target tissues.

Thus, the allergen induces an IgE-mediated and Th2-cell immune response. Allergens are almost always low-molecular proteins, many of which can be found among air particles. Allergens, including house dust, house dust mite excrement, pet dung, plant pollen (trees, grasses, weeds) and mold, are often responsible for the development of acute and chronic allergic reactions.

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Pathological physiology of atopic and allergic conditions

After the allergen combines with IgE, histamine is released from the intracellular granules of mast cells; these cells are found throughout the body, but their highest concentration is in the skin, lungs, and gastrointestinal mucosa; histamine enhances the activation of immune cells and is the primary mediator of the clinical manifestation of atopy. Tissue damage and various chemical agents (e.g., irritants, opioids, surfactants) can cause histamine release directly, without the participation of IgE.

Histamine causes local vasodilation (erythema), which increases capillary permeability and causes edema (wheals); surrounding arteriolar vasodilation is mediated by a neuronal reflex mechanism (hyperemia) and stimulation of sensory endings (itching). Histamine causes contraction of smooth muscle cells of the airways (bronchoconstriction) and gastrointestinal tract (increased gastrointestinal motility), increases secretion of salivary and bronchial glands. When histamine is released systemically, it becomes an effective arteriolar dilator and can cause widespread peripheral blood stasis and hypotension; cerebral vasodilation may be a factor in the development of headache of vascular genesis. Histamine increases capillary permeability; the resulting loss of plasma and plasma proteins from the vascular bed may cause circulatory shock. This causes a compensatory increase in the level of catecholamines, the source of which are chromaffin cells.

Symptoms of atopic and allergic conditions

The most common symptoms include rhinorrhea, sneezing, nasal congestion (upper respiratory tract involvement), dyspnea and dyspnea (lower respiratory tract involvement), and itching (eyes, skin). Symptoms include swelling of the nasal turbinates, pain in the accessory sinuses on palpation, dyspnea, conjunctival hyperemia and edema, and lichenification of the skin. Stridor, dyspnea, and sometimes hypotension are life-threatening signs of anaphylaxis. In some children, chronic allergic lesions are indicated by a narrow and highly arched palate, a narrow chin, an elongated upper jaw with a deep bite (allergic face).

Diagnosis of atopic and allergic conditions

A thorough history is usually more reliable than testing and screening. The history includes frequency and duration of attacks, changes over time, triggers if known, relationship to seasons or a specific situation (e.g., predictable onset during pollen season; after exposure to animals, hay, dust; during exercise; in specific locations), family history of similar symptoms or atopic disorders; response to treatment. Age of onset may be important in diagnosing asthma, since childhood asthma is atonic, whereas asthma that begins after age 30 is not.

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Non-specific tests

Certain tests can confirm or deny that the symptoms are allergic in nature.

A complete blood count is performed to detect eosinophilia in all patients except those receiving glucocorticoids; these drugs decrease eosinophil levels. A white blood cell count of 5–15% eosinophils suggests atopy but does not identify its specificity; 16–40% eosinophils may reflect both atopy and other conditions (eg, drug hypersensitivity, cancer, autoimmune conditions, parasitic infections); 50–90% eosinophils are not a sign of atopic disorders but rather of hypereosinophilic syndrome or the presence of migratory helminth larvae of the internal organs. The total white blood cell count is usually normal.

Conjunctival, nasal secretions, or saliva may be examined for leukocytes; detection of any number of eosinophils suggests Th2-mediated allergic inflammation.

Serum IgE levels are elevated in atopic conditions, but this is not a serious diagnostic sign, since they can be increased in parasitic infections, infectious mononucleosis, autoimmune conditions, drug allergies, immunodeficiency states (hyper-IgE syndrome, Wiskott-Aldrich syndrome), and some forms of multiple myeloma. Determination of IgE levels is useful for guiding subsequent therapy in case of allergic bronchopulmonary aspergillosis.

Specific tests

Skin tests use a standardized concentration of antigen injected directly into the skin; special tests are performed when a careful history and general examination have not revealed the cause of the symptoms. Skin tests are more informative in diagnosing rhinosinusitis and conjunctivitis than in diagnosing allergic asthma or food allergies; the negative response to food allergies is very high. The most commonly used antigens are pollen (tree, grass, weed), mold, house dust mite, animal dung and serum, insect venom, food, and β-lactam antibiotics. The choice of antigen to be administered is based on the history and geographic location. Two technologies can be used: subcutaneous (injection) and intradermal. The former method allows for the detection of a larger number of allergens. The intradermal test is more sensitive but less specific; It can be used to assess sensitivity to an allergen when the subcutaneous test results are negative or questionable.

In the subcutaneous test, a drop of antigen extract is applied to the skin and the skin is then stretched and punctured or pierced through the drop of extract with the tip of a 27-gauge needle at a 20° angle or with an approved device. In the intradermal technique, the extract is injected intradermally with a 0.5- or 1-mm syringe and a 27-gauge needle with a short bevel to create a 1- or 2-mm wheal (usually about 0.02 ml). Both subcutaneous and intradermal tests should include the injection of another solution as a negative control and histamine (10 mg/ml for the subcutaneous test, 0.01 ml in a 1:1000 solution for the intradermal test) as a positive control. For patients with a rare generalized reaction (less than once a year) to the tested antigen, the study begins with a standard reagent diluted 100 times, then 10 times, and finally, the standard concentration. The test is considered positive if a blister and hyperemia appear, with the blister diameter being 3-5 mm larger than in the negative control after 15-20 minutes. A false-positive response occurs with dermographism (blisters and hyperemia are provoked by stroking or scarifying the skin). A false-negative response occurs with improper storage or violation of the expiration date of the allergen extract or with the use of certain drugs (e.g., antihistamines) that suppress reactivity.

Radioallergosorbent testing (RAST) detects the presence of allergen-specific serum IgE and is used when skin testing is contraindicated, such as generalized dermatitis, dermographism, a history of anaphylactic reaction to an allergen, or the need to take antihistamines. A known allergen in the form of an insoluble polymer-allergen conjugate is mixed with serum and detected using ¹²⁵ I-labeled anti-1gE antibodies. Any allergen-specific IgE in the serum binds to the conjugate and is detected by measuring the amount of ¹²⁵ I-labeled antibodies.

Provocation tests involve direct contact of the mucous membranes with the allergen and are used in patients in whom a reaction needs to be documented (e.g., to establish occupational exposure or disability) and sometimes to diagnose food allergy. Ophthalmologic testing has no advantages over skin testing and is rarely performed. Nasal or bronchial administration of the provocative agent is also a possible test method, but bronchial provocation is used only if the clinical significance of a positive skin test is unclear or no antigen extracts are available (e.g., occupational asthma).

Treatment of atopic and allergic conditions

Environmental control

Removing or preventing contact with the allergen is the basis of allergy treatment.

Therefore, preference should be given to pillows with synthetic fibers and a dense cover on the mattresses; it is necessary to wash bed linen frequently in hot water; exclude soft upholstery of furniture, soft toys, carpets, contact with pets; engage in the fight against cockroaches; it is also recommended to use dehumidifiers in toilets, basements and other poorly ventilated, damp rooms. Other measures may include treating living spaces with vacuum cleaners and filters using high-efficiency particulate air (HEPA), eliminating food allergens, limiting pets to certain rooms, frequent wet cleaning of furniture and carpets. Additional non-allergenic triggers of allergic reactions (cigarette smoke, strong odors, irritating smoke, air pollution, low temperatures, high humidity) should be excluded or strictly controlled.

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Antihistamines

Antihistamines do not affect the production or metabolism of histamine, but block its receptors. H2 blockers are the mainstay of therapy for allergic diseases. H2 blockers are used primarily to suppress gastric acid secretion and are of limited value in the treatment of allergies; they may be used in certain atopic disorders, especially chronic urticaria.

Oral H2 blockers provide symptomatic treatment of various atopic and allergic disorders (seasonal hay fever, allergic rhinitis, conjunctivitis, urticaria, other dermatoses, minor reactions to incompatible blood transfusions and radiocontrast agents); they are less effective in allergic bronchoconstriction and vasodilation. Onset of action is usually noted within 15-30 minutes, peaking within 1 hour, duration of action is usually 3-6 hours.

Oral H2 blockers may be sedative or nonsedative (with less sedative being preferred). Sedating antihistamines are widely available without a prescription. All of these drugs have significant sedative and anticholinergic effects; however, they also have limitations when used in the elderly, in patients with glaucoma, incipient prostatic hyperplasia, constipation, or dementia. Nonsedating (non-anticholinergic) antihistamines are preferred unless sedation is needed (e.g., nighttime treatment of allergies or short-term treatment of insomnia in adults or nausea in younger patients). Anticholinergic effects may also partially justify the use of sedating antihistamines for symptomatic treatment of rhinorrhea in acute respiratory infections.

Antihistamine solutions can be used intranasally (azelastine for rhinitis) or in the form of eye drops (azelastine, emedastine, ketotifen, levocabastine, olopatadine for conjunctivitis). Diphenhydramine is also available for topical use, but is not recommended for use; its effectiveness has not been proven, it can cause drug allergy in young children who are simultaneously taking oral H2 blockers; anticholinergic intoxication can develop.

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Mast cell stabilizers

Examples of this group of drugs include cromolyn and nedocromil. These drugs block the release of mediators from mast cells; they are used when other drugs (antihistamines, topical glucocorticoids) are ineffective or poorly tolerated. Ophthalmic forms are also used (e.g., lodoxamide, olopatadine, pemirolast).

Anti-inflammatory drugs.

NSAIDs are ineffective. Glucocorticoids can be given intranasally or orally. Oral glucocorticoids are used for systemic severe but self-limited allergic disorders (eg, seasonal asthma flare-ups, severe widespread contact dermatitis) and for the treatment of conditions refractory to current therapy.

Antileukotriene drugs are used to treat mild persistent asthma and seasonal allergic rhinitis.

Anti-1gE antibodies (omalizumab) are used to treat moderate to persistent or severe asthma that is refractory to standard therapy; this drug can be used to treat refractory allergic rhinitis.

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Immunotherapy

Contact with an allergen in gradually increasing doses (hypo- or desensitization) by injection or in large doses sublingually can induce tolerance and is used when contact with the allergen cannot be avoided and drug therapy does not give the desired results. The mechanism is unknown, but may be associated with the induction of IgG, which competes with IgE for the allergen and blocks the binding of IgE to their receptors on mast cells; or it may be associated with the induction of interferon γ, IL-12 and cytokines secreted by TM lymphocytes or the induction of regulatory T lymphocytes.

To achieve the full effect, injections should be given monthly. The usual starting dose is 0.1 to 1.0 biologically active units (BAU), depending on the initial sensitivity, and then increased weekly or every other week by 2 times per injection until the maximum tolerated concentration is reached. Patients should be observed for 30 minutes during each dose increase because of the risk of anaphylaxis after injection. The maximum dose should be given every 4 to 6 weeks year-round; such treatment is better than pre-season or seasonal treatment even for seasonal allergies. Allergens used in this treatment are those to which contact cannot usually be avoided: pollen, house dust mite, mold, and the venom of stinging insects. Insect venom is standardized by weight, the usual starting dose is 0.01 mcg and the usual maintenance dose is 100 to 200 mcg. Desensitization to pet dander is commonly used for patients who cannot avoid exposure to the allergen (veterinarians, laboratory workers), but there is insufficient evidence to support its benefit. Food desensitization is not indicated.

Inhaled nasal glucocorticoids and mast cell membrane stabilizers

Preparation	Dosage per injection	Initial dose	Number of doses in a can (per nostril)
Inhaled nasal glucocorticoids
Beclomethasone dipropionate	42mcg	> 12 years: 1 spray 2 to 4 times daily. 6-12 years: 1 spray 2 times a day	200
Budesonide	32mcg	6 years: 2 sprays 2 or 4 times a day
Flunisolide	50mcg	6-14 years: 1 spray in each nostril 3 times daily or 2 sprays in each nostril 2 or 3 times daily	125
Fluticasone	50mcg	4-12 years: 1 spray in each nostril once daily. > 12 years: 2 sprays in each nostril once daily.	120
Triamcinolone acetonide	55mcg	> 6 years: 2 sprays 1 time per day	100
Systemic glucocorticoids
Dexamethasone	84mcg	6-12 years: 1-2 sprays 2 times a day. > 12 years: 2 sprays 2 or 4 times a day	170
Mast cell stabilizers
Cromolyn	5.2 mg	6 years: 1 spray 3 or 4 times a day
Nedocromil	1.3 mg	6 years: 1 spray in each nostril 2 times daily

Desensitization to penicillin and foreign (xenogenic) serum can be performed.

Side effects are usually associated with overdose, sometimes with careless administration of the drug intramuscularly or intravenously, and are manifested by a variety of symptoms from mild cough or sneezing to generalized urticaria, severe asthma, anaphylactic shock and sometimes death. They can be prevented by a very slight increase in the dose, repetition or reduction of the dose in case the local reaction to the previous injection was excessive (2.5 cm in diameter), reduction of the dose when using fresh extracts. It is recommended to reduce the dose of pollen preparations during the flowering period.