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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-.

Atopy
Authors

Angel A. Justiz Vaillant1; Arif Jan2.

Affiliations
1 University of the West Indies
2 Drexel University

Last Update: November 6, 2019.

Introduction
Atopy is a predisposition to respond immunologically to diverse antigens/allergens, leading to CD4+ Th2 differentiation
and overproduction of immunoglobulin E (IgE). The clinical consequence of this is the propensity to develop
hypersensitivity reactions to allergens. Allergic bronchial asthma and allergic rhinitis are the most common
manifestations of atopy followed by atopic dermatitis and food allergy. Two or more clinical diseases can coexist in an
individual at the same time or at different times.

Other diseases described as atopic are allergic conjunctivitis, IgE-mediated drug allergy, insect bites, urticaria and
angioedema, and anaphylactic shock.[1][2][3][4]

Etiology
The etiology of atopy is unknown. Twin and epidemiological studies, as well as family and animal experiments, provide
striking evidence that the genetic factors play a crucial role in the propensity for atopy, regulating the total IgE synthesis,
and in the production of IgE antibodies to specific epitopes. The inheritance of several genes influences the tendency to
overproduce IgE, and this runs in families as shown clearly in the autosomal transmission of allergy, but the full
inheritance pattern is believed to be multigenic.[5]

A theory that explains the genesis of atopy suggests that it may arise through abnormal regulation by T helper cells and
suppressor T lymphocytes that should help in the production of IgE by plasma cells.[6][7]

Examples of chromosomal locations and genes associated with atopy are 5q associated with cytokine gene cluster (IL-3,
IL-4, IL-5, IL-13, CD14, beta-2-adrenergic receptor, and GM-CSF). IL-4 and IL-13 promote IgE switching, and IL-5
stimulates eosinophil growth and activation. Beta-2-adrenergic receptors regulate contraction of bronchial smooth
muscles. The chromosome 6p houses MHC class II, and some of the alleles regulate T cell responses to environmental
antigens or allergens. The chromosome 11q gene (high-affinity IgE receptor beta-subunit) that mediates mast cell
activation. Chromosome 12q houses genes for stem cell factor (intervene in mast cell growth and differentiation), IFN-
gamma (inhibits IL-4 synthesis) and STAT6 (mediates IL-4 signal transduction). Other genes associated with atopy are
IL-4 receptor alpha chain, DPP10 (a protein that regulates chemokine and cytokine activity), ADAM33
metalloproteinase, which is involved in airway remodeling, and CD80/CD86 located in 3q and RANTES in 17q are
genes thought to be involved in atopy. Finally, PHF11 in 13q encodes for a transcriptional regulator involved in the
clonal expansion of B cells and immunoglobulin expression.[8][9][10][11]

Nonspecific triggers of asthma include infections (viral respiratory infections), climatic factors (ozone, cold air, and
SO2), physiologic factors (exercise, hyperventilation, psychological factors) and ingestants (aspirin and nonsteroidal
anti-inflammatory drugs).

There is a list of occupational allergens causing IgE-mediated allergic asthma that includes animal products (cows, pigs,
mice, dogs, cats, and horses), insect dusts (mealworms, storage mites, cockroaches, bees, and flies), plant products (dust,
flours, grain and cotton dusts), fruits, seeds, leaves and pollens (castor beans, tobacco and weeping fig), vegetable, dusts,
gums and extracts (western red, California redwood, and exotic woods), microbial agents (fungal allergens, alginates,
protozoa, bacteria, and fungi), enzymes (papain, hog trypsin, pancreatic extracts, subtilisin, and pineapple bromelain),
therapeutic agents (penicillins, tetracycline, cephalosporins, sulfonamides, and spiramycin), sterilizing agents
(chloramides), inorganic chemicals (metal fumes and salts, aluminum, cobalt, fluoride, nickel, platinum, vanadium, and
zinc) and organic chemicals (amines, anhydrides, and azodicarbonamide).[10]

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Epidemiology
Atopy affects a significant portion of the general population, usually estimated at 10 to 30% in developed countries.
About 80% of atopic individuals have a family history of allergy compared with only 20% of the average population. In
monozygotic twins, there is only 50% concordance. The susceptibility for atopic diseases is genetic, but rather than one
or two causative dominant genes evidence suggests that there are many genes with moderate effects involved.[12]

Allergic rhinitis occurs in 10% to 12% of the US population. The prevalence and morbidity rate is due to the geographic
distribution of common allergens including dust mite and allergenic plants. Both sexes are equally affected. The
prevalence of bronchial asthma varies worldwide. It is a common disease that affects 5% of the population of Western
countries. It causes in the US above 3000 deaths per year. Increasing mortality and morbidity rates occur despite
substantial advances in immunotherapy.[13][14] There were 8.4 million children with asthma in the U.S. in 2014, and
11.1% lived in poor-urban areas.[15]

Pathophysiology
The pathophysiology of atopy characteristically demonstrates by mast cell activation. Antigen binding to IgE cross-links
Fc epsilon RI proteins on mast cells. It activates protein tyrosine kinases (Lyn and Syk) that in turn cause activation of a
MAP kinase cascade and a phosphatidylinositol-specific phospholipase C, which catalyzes the release of the following
molecules: IP3 and DAG from membrane PIP2. Inositol trisphosphate (IP3) causes the release of intracellular calcium
from the endoplasmic reticulum. DAG and calcium activate PKC that phosphorylates substrates such as myosin light
chain molecule and thus leads to degradation and release of preformed mediators. MAP kinases and calcium react to
activate the enzyme cytosolic phospholipase A2, which stimulates the synthesis of lipid mediators including PGD2,
LTC4, LTD4, and LTE4. Ras/MAP kinases in the presence of calcium and PKC cause cytokine gene expression, which
releases TNF and other cytokines (IL-4, IL-5, IL-6, IL-13 among others). Lipid mediators, cytokines and histamine
cause an inflammatory response.[16][17][18]

Basophils and mast cell mediators include biogenic amines and enzymes stored preformed in granules, cytokines and
lipid mediators, which are mainly newly synthesized on cell activation. Histamine and other biogenic amines, as well as
lipid mediators, induce vascular leakage, and intestinal hypermotility, which are all components of immediate allergic
responses. Cytokines and lipids mediators add to inflammation that is part of a late-phase reaction. Enzymes presumably
contribute to tissue damage. Activated eosinophils release enzymes as well as cationic proteins that are toxic to parasites
and host cells. The thinking is that some eosinophil granule enzymes participate in tissue damage in chronic allergic
disorders.[19][20][21]

Defective lymphocyte regulation is a possible explanation in allergic dermatitis. Delayed hypersensitivity skin test
responses to allergens, in vitro lymphocyte responses to mitogens or allergens, and autologous mixed lymphocyte
reactions have all been reported to be defective. It has been reported in atopic dermatitis an increased susceptibility to
vaccinia virus, molluscum contagiosum, warts, herpes simplex virus, and dermatophyte skin infections are in harmony
with a defect in the T lymphocyte effector mechanism. There are suggestions that an anomalous or defective CD4+
helper T cell population could explain the failure of CD8+ T cells to function as immunosuppressors of the production of
IgE.[22][23]

Histopathology
Atopy presents with a histopathologically characteristic wheal and flare reaction in the skin, which is in response to an
allergen-stimulated release of mediators from mast cells, local blood vessels that dilate and become leaky to proteins and
fluids, which produces local swelling and redness.[24]

Histologic characteristics of bronchial asthma show a diseased bronchus with excessive mucus production, many
submucosal inflammatory cells, including lymphocytes and eosinophils, thickened basement membrane, and smooth
muscle hypertrophy.

History and Physical

In the following atopic diseases, there is a history of atopy (hypersensitivity to many allergens, and elevated IgE serum
levels). Patients are symptom-free in the absence of exposure.

Atopic rhinitis

Characterized by nasal congestion

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Rhinorrhea

Sneezing

Itching of the nose

Post-nasal drainage

Dry cough

Ocular symptoms

Rhinoscopy shows a pale, swollen nasal mucosa with watery secretions

The conjunctivae are hyperemic and edematous

Allergic asthma symptoms

Asthma may begin at any age

Frequent attacks of wheezing and dyspnea associated with chest tightness and coughing(often nocturnal in
children) at times productive of thick and tenacious sputum

Fatigue

Malaise

Use of accessory muscles of respiration

The lung fields are hyper-resonant

Diminished breath sounds, rhonchi, and wheezes on auscultation

The expiratory phase is prolonged

In severe attacks breath, sounds and wheezing may both be absent

Atopic dermatitis

The disease almost always begins in infancy

Itching that worsens at night and exacerbates by irritants such as wool

There is a strong family history of atopy

Scratching and rubbing cause the typical eczematous skin eruption to flare

Ingestion of allergenic food may cause exacerbations

The skin is typically dry and scaly

Presence of active skin lesions with prurigo and erythema

Chronic lesions are thickened and lichenified

Distribution of the lesions is dependent on age - in childhood mostly affects the forehead and cheeks

Food allergy can manifest as

Rhinoconjunctivitis

Asthma

Respiratory symptoms alone are rare

Usually part of systemic anaphylaxis

Hypotension

Arrhythmias

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Nausea and vomiting

Abdominal cramping or diarrhea

Evaluation
The evaluation of immediate hypersensitivity includes obtaining a complete blood cell count, assessment of
immunoglobulin IgE and skin prick test.[25]

Quantitative Serum Immunoglobulins

IgM, IgG, and IgA

Total Leukocyte Count and Differential

Hb (decreased in autoimmune hemolytic anemia)

Eosinophilia

Lymphocyte studies (CD4/CD8 count and suppressor T cells count that may be lower than the standard value)

Allergic test

Skin prick tests utilizing various allergens from animal, plants, food, pathogens and environmental pollutants

The radioallergosorbent test (RAST): Use to determine specific IgE antibodies

Other tests

Serum protein electrophoresis (to rule out IgE myeloma)

Stool examination (for intestinal parasitism)

Appropriate exclusion diet and blinded provocation (for food allergy diagnostic clarification)

Chest X-ray (in bronchial asthma)

Treatment / Management
Allergic rhinitis

The treatment of allergic rhinitis consists of environmental measure to prevent allergen exposure, drugs, and
desensitization. As an allergic disease, the prophylactic treatment by avoidance of allergens is the most potent means of
treatment. However, avoidance is not always possible because of that drugs are needed to control symptoms or the use of
desensitization.

Environmental measures include the avoidance of an allergen by a clinical history of allergy and not because of a
positive skin test or RAST alone. The environmental control covers the removal of household pets, cleaning of house
dust by frequent cleaning, avoidance of toys and other objects. The use of air-cleaning devices may be helpful.
Prevention of pollen and outdoor mold growth is necessary.

Antihistamines are the most regularly used drugs in allergy rhinitis and should be administered with care for the
avoidance of side effects although new nonsedating antihistamines are available that restrain most common side effects.
Orally administered nasal decongestants may be helpful in combination with antihistamines. For treating allergic
conjunctivitis antihistaminic eyes, drops are critical. The treatment with cromolyn by nasal spray four times daily is
beneficial and free of immediate or long-term toxicity. Systemic corticosteroids are remarkably effective in reducing
symptoms of allergic rhinitis, but since it is a chronic and benign condition should be used with much care.
Desensitization (allergen injection therapy) should be given to patients whose symptoms are uncontrolled despite
appropriate previous therapeutic measures.[26]

Allergic asthma

It is a manifestation of atopy localized in the bronchus. There is a release of critical mediators including histamine,
leukotrienes, and cytokines including IL-4, IL-5, IL-13, TNF and eosinophil chemotactic factor. The aim of symptomatic
asthma is controlling the hyperirritable bronchial mucosa using environmental measures, drugs, and other therapies.

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The drug treatment of bronchial asthma includes environmental control as referred to in atopic rhinitis. The drug
treatment includes the use of sympathomimetic beta-adrenergic bronchodilators drugs, which are useful and use in acute
attack or for long term management. Epinephrine can be successfully given in a dose of 0.2-0.5 mL subcutaneously.
Albuterol, metaproterenol, pirbuterol, and isoetharine are selective beta-adrenergic bronchodilators dosed via inhalation
in the aerosol. Theophylline is a potent bronchodilator when used in combination with sympathomimetic medication.
Intravenous theophylline can be used in a dosage of 250 to 500 mg and administered swiftly in an acute asthmatic attack.
Glucocorticoids are remarkably successful in the treatment of allergic asthma. Although their effectiveness should be
used in asthma only when other therapeutic options have failed. A dose of 30 to 60 mg of prednisone daily is usually
enough.[15]

Cromolyn sodium (20 mg) can be given in a metered-dose inhaler and for long-term prophylactic therapy. It never
reverses an acute attack. Antibiotics are an option in allergic asthma if secondary bacterial bronchitis or
bronchopneumonia occurs. Hydration and expectorants are effective for thick sputum. The effectiveness of
desensitization in allergic asthma works well as in allergic rhinitis. An example of it is injection treatment in pollen hay
fever. Antileukotrienes such as montelukast and zafirlukast can be administered in allergic asthma and atopic rhinitis.

Atopic dermatitis

Atopic dermatitis presents as a chronic skin disease requiring proper skin care, environmental control, drugs and
avoidance of the allergen. The most preventive measure is the use of nonirritating topical lubricants for skin itching.
Topical steroids are effective when skin involvement is less severe, but in systemic eczema, systemic corticosteroids are
necessary, often initiating with a high dosage and then tapering until achieving a therapeutic effect. Oral antihistamines
help to control the itching. Patients should not engage in frequent bathing, or use irritating fabrics, and harsh detergents.
If infection occurs, an appropriate antibiotic is necessary.[27]

Food allergy

The treatment of a food allergy consists of a strict elimination of offending allergen. Having an emergency care plan and
a written anaphylaxis action plan is of utmost importance. A form of self-injectable epinephrine and a medical alert
bracelet is critical to signal healthcare professionals of what is going on. The most common food allergens in children
are cow's milk, soy wheat, egg, and peanut that account for 91% of reactions. In adults, the most common allergens are
fish, shellfish, peanuts, tree nuts, eggs, fruits, and vegetable.[28]

Differential Diagnosis
Atopy should be differentiated from diseases associated with elevated total serum IgE, which include:

Allergic bronchopulmonary aspergillosis

Parasitic diseases

Immunodeficiency with ataxia-telangiectasia

Hyper-IgE syndrome

Wiskott-Aldrich syndrome

IgE myeloma

Thymic alymphoplasia

Graft-versus-host reaction

Differential diagnosis of atopic rhinitis

Chronic nonallergic (vasomotor) rhinitis

Rhinitis medicamentosa

Infectious rhinitis

Vernal keratoconjunctivitis

Differential diagnosis of allergic bronchial asthma

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Pulmonary emphysema

Acute bronchiolitis

Cystic fibrosis

Aspiration of a foreign body

Airway obstruction caused by a congenital vascular anomaly

Cardiac asthma caused by left ventricular failure

Carcinoid tumors

Differential diagnosis of atopic dermatitis

Localized neurodermatitis (lichen simplex chronicus)

Allergic or irritant contact dermatitis

Seborrhea and dermatophytoses

Pompholyx (dyshidrosis)

Pertinent Studies and Ongoing Trials

A recent meta-analysis showed the use of multi-strain probiotics to be most useful for eczema prevention in
children.[29]

A study indicates that the administration subcutaneously of a single-dose of tralokinumab (150 to 600 mg),
a human monoclonal antibody in clinical development for atopic dermatitis and asthma, was well tolerated in
healthy Japanese volunteers. This study was a phase I, single-blind, randomized, placebo-controlled, and single
ascending-dose study, and supports the 300 mg dose selection for Japanese patients with asthma.[30]

Epicutaneous immunotherapy (EPIT) can be used to treat food allergy. EPIT activates the skin natural
desensitization pathway and offers a progressive, possibly sustained response. This immunotherapy provides
potential alternatives for atopic immunotherapy, which is less invasive and also carries a lower risk for systemic
reactions than oral immunotherapy.[31]

Oral immunotherapy consists of administering rising doses of a food antigen to food-allergic subjects, to provoke
a state of desensitization. Tolerability, efficacy, and safety remain an ongoing concern.[32]

Randomized placebo-controlled studies showed that ciclesonide, an inhaled corticosteroid, can initiate and
maintain disease control in individuals with persistent asthma of all disease severities.[33]

Randomized controlled trials (RCTs) exploring the capacity of vitamin D to stop acute respiratory infections have
yielded positive results. Vitamin D supplementation was safe, and it also protected against acute respiratory
infections overall in very deficient individuals and those subjects not receiving bolus doses as well as experienced
the benefit.[34]

Prognosis
Atopic individuals have a lifelong tendency for the development of allergic reactions as it is incurable. Nevertheless, the
manifestations of atopy often change over some time. Atopic dermatitis has a better prognosis and is treatable with some
success with immunotherapy. Allergic asthma has a prognosis that varies according to the persistence of the causative
environmental allergen, the IgE levels in blood or tissues, and the genetic makeup.

Systemic anaphylaxis is the occurrence of an immunoglobulin E mediated reaction simultaneously in multiple tissues.
The causative allergen is an insect venom, food or drug. The reaction is potentially fatal and can be evoked by a tiny
quantity of allergen. The prognosis of anaphylaxis is very poorly and requires immediate medical care.

Complications
Complications of allergic rhinitis - untreated cases can lead to:

Sinusitis
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Otitis media

Nasal polyps

Apnea

Complications of allergic bronchial asthma:

Pneumothorax

Subcutaneous emphysema

Complications of atopic dermatitis:

Secondary infections caused by Staphylococcus

Eczema herpeticum

Secondary contact dermatitis (due to antibiotics)

Hand dermatitis (by excessive contact with water)

Ophthalmic complications include atopic keratoconjunctivitis, keratoconus, and atopic cataracts

Anaphylaxis[35][36][37]:

It can lead to acute, life-threatening respiratory failure

It is a medical emergency and IgE mediated with massive and rapid release of histamines and leukotrienes from
mast cells

In severe cases acute laryngeal edema, bronchospasm, hypotension, cyanosis, and shock are present.

There is a list of drugs and additives that cause anaphylactoid reactions including nonsteroidal anti-inflammatory
drugs including aspirin, aminopyrine, fenoprofen, flufenamic acid, ibuprofen, indomethacin, and naproxen; opiate
narcotics including morphine, codeine, and meperidine; mannitol, radiographic iodinated contrast media, dextran,
curare, and d-tubocurarine

Anaphylactoid reactions should be treated similarly as anaphylaxis

Consultations

Allergy specialist

Dermatologist

Pulmonary physician

Immunologist

Deterrence and Patient Education

Patient education is crucial and in children involves educating parents especially to identify and avoid triggers in the first
place.

Patients should also receive counsel on how to manage the reactions initially and when to seek specialist help.

Enhancing Healthcare Team Outcomes

Atopy should be recognized earlier, often requires early identification by the pediatrician and early referral to an allergy
specialist for disease confirmation and management. Later on, pulmonologists and dermatologist input may be necessary
as well. The primary care provider, specialty-trained nurses, and pharmacists should educate the patient on keeping a
diary of allergens and carrying an epinephrine injector with them. All these professionals need to collaborate as an
interprofessional team to guide cases to the best possible outcome. [Level V] Additionally, these individuals should be
told to wear an ID bracelet if they have previously suffered from an anaphylactic reaction.

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Questions
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