Overview of Allergic and Atopic Disorders

Type I reactions (immediate hypersensitivity) are IgE-mediated. Antigen binds to IgE that is bound to tissue mast cells and blood basophils, triggering release of preformed mediators (eg, histamine, proteases, chemotactic factors) and synthesis of other mediators (eg, prostaglandins, leukotrienes, platelet-activating factor, cytokines). These mediators cause vasodilation, increased capillary permeability, mucus hypersecretion, smooth muscle spasm, and tissue infiltration with eosinophils, type 2 helper T (TH2) cells, and other inflammatory cells.

Overview of Type I Hypersensit...

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Type I hypersensitivity reactions develop < 1 hour after exposure to antigen.

Type I reactions underlie all atopic disorders (eg, atopic dermatitis, allergic asthma, rhinitis, conjunctivitis) and many allergic disorders (eg, anaphylaxis, some cases of angioedema, urticaria, latex and some food allergies). The terms atopy and allergy are often used interchangeably but are different:

• Atopy is an exaggerated IgE-mediated immune response; all atopic disorders are type I hypersensitivity disorders.

• Allergy is any exaggerated immune response to a foreign antigen regardless of mechanism.

Thus, all atopic disorders are considered allergic, but many allergic disorders (eg, hypersensitivity pneumonitis) are not atopic.

Atopic disorders most commonly affect the nose, eyes, skin, and lungs. These disorders include conjunctivitis, extrinsic atopic dermatitis (the most common type of eczema), immune-mediated urticaria, some forms of angioedema, acute latex allergy, some allergic lung disorders (eg, allergic asthma, IgE-mediated components of allergic bronchopulmonary aspergillosis), allergic rhinitis, and allergic reactions to venomous stings.

Type II reactions (antibody-dependent cytotoxic hypersensitivity) result when antibody binds to cell surface antigens or to a molecule coupled to a cell surface. The surface-bound antigen-antibody structure (as opposed to the circulating antigen-antibody complex in type III hypersensitivity) activates cells that participate in antibody-dependent cell-mediated cytotoxicity (eg, natural killer cells, eosinophils, macrophages), complement, or both. The result is cell and tissue damage.

Overview of Type II Hypersensi...

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Disorders involving type II reactions include hyperacute graft rejection of an organ transplant, Coombs-positive hemolytic anemias, Hashimoto thyroiditis, and anti–glomerular basement membrane disease (eg, Goodpasture syndrome).

Type III reactions (immune complex disease) cause inflammation in response to circulating antigen-antibody immune complexes deposited in vessels or tissue. These complexes can activate the complement system or bind to and activate certain immune cells, resulting in release of inflammatory mediators.

Consequences of immune complex formation depend in part on the relative proportions of antigen and antibody in the immune complex. Early in the immune response, there is excess antigen with small antigen-antibody complexes, which do not activate complement. Later, when antigen and antibody are more balanced, immune complexes are larger and tend to be deposited in various tissues (eg, glomeruli, blood vessels), causing systemic reactions. The isotype of induced antibodies changes during an immune response, and the isotype, glycosylation, size, and charge of the complex’s components contribute to the clinical response.

Overview of Type III Hypersens...

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Type III disorders include serum sickness, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), leukocytoclastic vasculitis, cryoglobulinemia, acute hypersensitivity pneumonitis, and several types of glomerulonephritis.

Type III reactions develop 4 to 10 days after exposure to antigen and, if exposure to the antigen continues, can become chronic.

Type IV reactions (delayed hypersensitivity) do not involve antibodies but are mediated by T cells.

Overview of Type IV Hypersensi...

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T cells, sensitized after contact with a specific antigen, are activated by continued exposure or reexposure to the antigen; they damage tissue by direct toxic effects or through release of cytokines, which activate eosinophils, monocytes and macrophages, neutrophils, or natural killer cells.

Disorders involving type IV reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis (SJS/TEN), drug rash with eosinophilia and systemic symptoms (DRESS), contact dermatitis (eg, poison ivy), subacute and chronic hypersensitivity pneumonitis, acute and chronic allograft rejection, the immune response to tuberculosis, and many forms of drug hypersensitivity.

By definition, an allergen induces type I IgE-mediated or type IV T-cell–mediated immune responses. Allergic triggers are almost always low molecular weight proteins; many of them can become attached to airborne particles.

Sources of allergens that most commonly cause acute and chronic allergic reactions (type I and type IV) include

• House dust mite feces

• Animal dander

• Pollens (tree, grass, weed)

• Molds

• Foods

• Insect saliva and venom (transmitted by bites and stings)

• Medications

• Household chemicals (eg, hydroxyisohexyl 3-cyclohexene carboxaldehyde, cinnamal, eugenol)

For type IV hypersensitivity reactions, medications are the most common cause.

Certain tests can suggest but not confirm an allergic origin of symptoms.

Complete blood count (CBC) may be done to detect eosinophilia if patients are not taking corticosteroids, which reduce the eosinophil count. However, CBC is of limited value because although eosinophils may be increased in atopy or other conditions (eg, drug hypersensitivity, cancer, inflammatory bowel disease, parasitic infection), a normal eosinophil count does not exclude allergy. Total white blood cell count is usually normal. Anemia and thrombocytosis are not typical of allergic responses and should prompt consideration of a systemic inflammatory disorder.

Conjunctival or nasal secretions or sputum can be examined for leukocytes; finding any eosinophils suggests that TH2-mediated inflammation is likely.

Total serum IgE levels are elevated in atopic disorders but are of little help in making a specific allergic diagnosis because they may also be elevated in parasitic infections, infectious mononucleosis, some autoimmune disorders, drug reactions, immunodeficiency disorders (hyper-IgE syndrome and Wiskott-Aldrich syndrome), IgG4-related disease, and in some forms of multiple myeloma. IgE levels are helpful for following response to therapy in allergic bronchopulmonary aspergillosis.

Skin testing uses standardized concentrations of antigen introduced directly into skin and is indicated when a detailed history and physical examination do not identify the cause and triggers for persistent or severe symptoms. Skin testing has higher positive predictive values for diagnosing allergic rhinitis and conjunctivitis than for diagnosing allergic asthma or food allergy; negative predictive value for food allergy is high (1).

The most commonly used antigens are pollens (tree, grass, weed), molds, house dust mite feces, animal danders and sera, insect venom, foods, and beta-lactam antibiotics. Choice of antigens to include is based on patient history and geographic prevalence.

Two skin test techniques can be used:

• Percutaneous (prick)

• Intradermal

The prick test can detect most common allergies; it is usually done first. The intradermal test is more sensitive but less specific; it can be used to evaluate sensitivity to allergens when prick test results are negative or equivocal.

For the prick test, a drop of antigen extract is placed on the skin, which is then tented up and pricked or punctured through the extract with the tip of a 27-gauge needle held at a 20° angle or with a commercially available prick device.

If no allergen is identified in the prick test, an intradermal test is done.

For the intradermal test, just enough extract to produce a 1- or 2-mm bleb (typically 0.02 mL) is injected intradermally with a 0.5- or 1-mL syringe and a 27-gauge short-bevel needle.

Prick and intradermal skin testing should include the diluent alone as a negative control and histamine (10 mg/mL for prick tests, 0.01 mL of a 1:1000 solution for intradermal tests) as a positive control. For patients who have had a recent (< 1 year) generalized reaction to the test antigen, testing begins with the standard reagent diluted 100-fold, then 10-fold, and then the standard concentration.

A test is considered positive if a wheal and flare reaction occurs and wheal diameter is 3 to 5 mm greater than that of the negative control after 15 to 20 minutes.

False positives occur in dermatographism (a wheal and flare reaction provoked by stroking or scraping the skin). False negatives occur when allergen extracts have been stored incorrectly or are outdated.

epinephrine.

Allergen-specific serum IgE tests use an enzyme-labeled anti-IgE antibody to detect binding of serum IgE to a known allergen. These tests are done when skin testing might be ineffective or risky—for example, when drugs that interfere with test results cannot be temporarily stopped before testing or when a skin disorder such as eczema, dermatographism, or psoriasis would make skin testing difficult. For allergen-specific serum IgE tests, the allergen is immobilized on a synthetic surface. After incubation with patient serum and enzyme-labeled anti-IgE antibody, a substrate for the enzyme is added; the substrate provides colorimetric, fluorescent, or chemiluminescent detection of binding. Allergen-specific IgE tests have replaced radioallergosorbent testing (RAST), which used 125-I-labeled anti-IgE antibody. Although the allergen-specific serum IgE tests are not radioactive, they are still sometimes referred to as RAST.

Provocative testing includes an oral challenge, which involves direct exposure of the mucosae to allergen; it is indicated for patients who must document their reaction (eg, for occupational or disability claims) and for excluding an IgE-mediated allergy in patients thought to be at low risk of allergy. This test is frequently done to exclude food and medication allergy. Other types of provocative testing include asking patients to exercise to diagnose exercise-induced asthma. Various provocative tests for physical urticaria can be done in the office; they include placing an ice cube on the skin for 4 minutes to diagnose cold-induced urticaria, asking patients to exercise to increase body temperature and thus confirm cholinergic urticaria, and placing a vortex (laboratory vibratory device) on a patient's arm or hand to identify mast-cell mediated vibratory urticaria.

Nasal and bronchial challenge are primarily research tools, but bronchial challenge is sometimes used when the clinical significance of a positive skin test is unclear or when no antigen extracts are available (eg, for work-related asthma).

1. 1. Patel G, Saltoun C. Skin testing in allergy. Allergy Asthma Proc 2019;40(6):366-368. doi:10.2500/aap.2019.40.4248

Severe allergic reactions (eg, anaphylaxis

If the airways are affected (eg, in angioedema), securing an airway is the highest priority. Treatment may include and/or endotracheal intubation.

Removal or avoidance of allergic triggers is the primary treatment and preventive strategy for allergy. However, when patients are sensitized to multiple allergens, complete avoidance is essentially impossible.

Antihistamines block histamine receptors; they do not affect histamine production or metabolism. There are 4 different histamine receptors: H1, H2, H3, and H4.

Antihistamines that block the H1 receptor (H1 blockers) are a mainstay of treatment for allergic disorders. H2 blockers are used primarily for gastric acid suppression and but are useful for certain allergic reactions; they may be indicated as adjunctive therapy for treatment of anaphylaxis, mastocytosis, and certain atopic disorders, especially chronic spontaneous urticaria.

Oral H1 blockers relieve symptoms in various atopic and allergic disorders (eg, seasonal hay fever, allergic rhinitis, conjunctivitis, urticaria, other dermatoses, minor reactions to blood transfusion incompatibilities); they are less effective for allergic bronchoconstriction and systemic vasodilation. Onset of action is usually 15 to 30 minutes, with peak effects in 1 hour; duration of action is usually 3 to 6 hours.

Oral H1 blockers are classified as

• First-generation: Sedating

• Second-generation: Nonsedating (better thought of as less sedating)

First-generation antihistamines are widely available without prescription. They easily cross the blood-brain barrier. All have significant sedative and anticholinergic properties; they pose particular problems for older patients and for patients with glaucoma, benign prostatic hyperplasia, constipation, orthostatic hypotension, delirium, or dementia.

Second-generation antihistamines are also widely available without prescription. They do not cross the blood-brain barrier as easily as first-generation antihistamines. Second-generation antihistamines are usually preferred.

Antihistamines may be given by various routes, including

• Oral (multiple—see table Oral H1 Blockers)

Mast cell stabilizers block the release of mediators from mast cells.

Mast cell stabilizers are used when other medications (eg, antihistamines, topical corticosteroids) are ineffective or not well-tolerated. They are also frequently used in patients with mast cell disease when mast activation and release of mediators overwhelms conventional antihistamines.

These medications may be given

Corticosteroids can be given intranasally (see tables Intranasal Corticosteroids and Intranasal Mast Cell Stabilizers) or orally.

Oral corticosteroids are indicated for the following:

• Allergic disorders that are severe but self-limited and not easily treated with topical corticosteroids (eg, acute asthma exacerbations, severe widespread contact dermatitis)

• Disorders refractory to other measures

Ocular corticosteroids are used only when an ophthalmologist is involved because infection and increased intraocular pressure are potential adverse effects.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are typically not useful, with the exception of topical forms used to relieve conjunctival injection and itching due to allergic conjunctivitis.

Leukotriene inhibitorsMedication Treatment of Asthma):

Anti-IgE antibody () is indicated for the following:

• Moderately persistent or severe asthma refractory to standard treatment

• Chronic idiopathic urticaria refractory to antihistamine therapy

• Nasal polyps

• Type 1 allergic reactions (including anaphylaxis) that may occur with accidental exposure to 1 or more foods in patients ≥ 1 year old with IgE-mediated food allergy

Exposure to allergen in gradually increasing doses (hyposensitization or desensitization) via injection or orally or in high doses sublingually can induce tolerance. This therapy is indicated when allergen exposure cannot be avoided and pharmacotherapy is inadequate.

Mechanism is unknown but may involve induction of the following:

• IgG antibodies, which compete with IgE for allergen or block IgE from binding with mast cell IgE receptors

• Interferon-gamma, IL-12, and cytokines secreted by TH1 cells

• Regulatory T cells

For full effect, injections are initially given once or twice a week. Dose typically starts at 0.1 to 1.0 biologically active units (BAU), depending on how sensitive the patient appears to be, and is increased weekly or every 2 weeks by ≤ 2 times with each injection until the maximum tolerated dose (the dose that begins to elicit moderate adverse effects) is established. Patients should be observed for about 30 minutes postinjection during dose escalation because anaphylaxis may occur after injection. Subsequently, injections of the maximum tolerated dose should be given every 2 to 4 weeks year-round; year-round treatment is better than preseasonal or coseasonal treatment, even for seasonal allergies.

Allergens used are those that typically cannot be avoided:

• Pollens

• House dust mite feces

• Molds

• Venom of stinging insects

Insect venoms are standardized by weight. Animal dander desensitization is ordinarily limited to patients who cannot avoid exposure (eg, veterinarians, laboratory workers), but there is little evidence that it is useful. Desensitization for peanut is available and has been successful in about 60 to 80% of the cases (1). Desensitization for penicillin and certain other medications and for foreign (xenogeneic) serum can be done. Desensitization for medication allergies is successful in most cases (2).

Adverse effects are most commonly related to overdose, occasionally via inadvertent IM or IV injection of a dose that is too high, and range from mild cough or sneezing to generalized urticaria, severe asthma, anaphylactic shock, and, rarely, death. Adverse effects can be prevented by the following:

• Increasing the dose in small increments

• Repeating or decreasing the dose if local reaction to the previous injection is large (≥ 2.5 cm in diameter)

• Reducing the dose when a fresh extract is used

Sublingual immunotherapy with grass pollen, ragweed, or house dust mite allergen extracts can be used for allergic rhinitis when it is induced by these allergens. The first dose is given in a health care setting; patients should be observed for 30 minutes after administration because anaphylaxis may occur. If the first dose is tolerated, patients take subsequent doses daily at home. In adults, the initial dose is not increased, but in children and adolescents aged 10 to 17 years, the dose is increased over the first 3 days. In patients with grass pollen or ragweed allergy, treatment is initiated at least 3 months before the onset of each grass pollen or ragweed season and maintained throughout the season.

The anaphylaxis rate to commercially available sublingual immunotherapy extracts has been reported as 0.02 to 0.03% vs near 0.1% with subcutaneous immunotherapy (SCIT) (3).

Oral immunotherapy for peanut allergy uses defatted peanut flour. Dose escalation is done using 5 incremental doses from 0.5 mg to 6 mg over one day given in a health care setting. This initial regimen is followed by a daily dose starting at 3 mg and increasing by 50 to 100% every 2 weeks over 22 weeks before reaching the maintenance dose of 300 mg once a day. Each increase in dose is given in a health care setting. If the initial dose is tolerated, subsequent doses are taken daily for 2 weeks; they can be taken at home. After patients successfully tolerate the 300-mg dose in a health care setting, they must take the 300-mg daily dose indefinitely to maintain desensitization.

For pregnant women with environmental allergies and sinopulmonary symptoms, avoidance of the allergen is the best way to control symptoms. If symptoms are severe, an antihistamine intranasal spray is recommended. An oral antihistamine should be used only if antihistamine intranasal sprays are inadequate.

During breastfeeding, nonsedating antihistamines are preferred. Sedating antihistamines can be used, but they may cause drowsiness and irritability in the infant. If a sedating antihistamine is required, the infant should be monitored for these effects.

1. 1. Alghamdi R, Alshaier R, Alotaibi A, et al: Immunotherapy Effectiveness in Treating Peanut Hypersensitivity: A Systemic Review. Cureus 14(2):e21832, 2022. doi:10.7759/cureus.21832

2. 2. Brennan PJ, Rodriguez Bouza T, Hsu FI, Sloane DE, Castells MC: Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to treatment. J Allergy Clin Immunol 124(6):1259–1266, 2009. doi:10.1016/j.jaci.2009.09.009

3. 3. Zeiger RS, Schatz M, Pomichowski ME, et al: Real-world assessment of anaphylaxis and eosinophilic esophagitis with 12 SQ house dust mite SLIT-tablet sublingual immunotherapy. J Allergy Clin Immunol Glob 3(3):100250, 2024. doi:10.1016/j.jacig.2024.100250