Continuing Education Activity

Atopy is a predisposition to an immune response against diverse antigens and allergens leading to CD4+ Th2 differentiation and overproduction of immunoglobulin E (IgE). The clinical consequence is an increased propensity to hypersensitivity reactions. Allergic bronchial asthma and allergic rhinitis are the most frequent manifestations of atopy, followed by atopic dermatitis and food allergy. Other diseases described as atopic include allergic conjunctivitis, IgE-mediated drug allergy, urticaria and angioedema, and anaphylactic shock. This activity describes the evaluation and management of patients with the most common manifestations of atopy and highlights the role of the interprofessional team in improving care for these patients.

Objectives:

• Describe the pathophysiology of atopy.
• List the signs and symptoms of an anaphylactic reaction.
• Identify treatment options for people with food allergies.
• Outline the importance of improving care coordination amongst interprofessional team members to improve outcomes for patients affected by atopy.

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]

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 
• 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
• 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.

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

• 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
• 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.