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]
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]
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]
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]
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.
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
Allergic asthma symptoms
Atopic dermatitis
Food allergy can manifest as
The evaluation of immediate hypersensitivity includes obtaining a complete blood cell count, assessment of immunoglobulin IgE and skin prick test.[25]
Quantitative Serum Immunoglobulins
Total Leukocyte Count and Differential
Allergic test
Other tests
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]
Atopy should be differentiated from diseases associated with elevated total serum IgE, which include:
Differential diagnosis of atopic rhinitis
Differential diagnosis of allergic bronchial asthma
Differential diagnosis of atopic dermatitis
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 of allergic rhinitis - untreated cases can lead to:
Complications of allergic bronchial asthma:
Complications of atopic dermatitis:
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.
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.
[1] | Celakovská J,Bukac J,Ettler K,Vaneckova J,Krcmova I,Ettlerova K,Krejsek J, Evaluation of Peripheral Blood Eosinophilia in Adolescent and Adult Patients Suffering from Atopic Dermatitis and the Relation to the Occurrence of Allergy to Aeroallergens. Indian journal of dermatology. 2019 Jan-Feb; [PubMed PMID: 30745633] |
[2] | Heffler E,Blasi F,Latorre M,Menzella F,Paggiaro P,Pelaia G,Senna G,Canonica GW, The Severe Asthma Network in Italy: Findings and Perspectives. The journal of allergy and clinical immunology. In practice. 2018 Oct 25; [PubMed PMID: 30368004] |
[3] | Campo P,Eguiluz-Gracia I,Bogas G,Salas M,Plaza Serón C,Pérez N,Mayorga C,Torres MJ,Shamji MH,Rondon C, Local allergic rhinitis: Implications for management. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2019 Jan; [PubMed PMID: 29900607] |
[4] | Katainen E,Kostamo K,Virkkula P,Sorsa T,Tervahartiala T,Haapaniemi A,Toskala E, Local and systemic proteolytic responses in chronic rhinosinusitis with nasal polyposis and asthma. International forum of allergy [PubMed PMID: 25653042] |
[5] | Qi S,Liu G,Dong X,Huang N,Li W,Chen H, Microarray data analysis to identify differentially expressed genes and biological pathways associated with asthma. Experimental and therapeutic medicine. 2018 Sep; [PubMed PMID: 30186379] |
[6] | Kim JH,Lee SY,Kang MJ,Yoon J,Jung S,Cho HJ,Kim HB,Hong SJ, Association of Genetic Polymorphisms with Atopic Dermatitis, Clinical Severity and Total IgE: A Replication and Extended Study. Allergy, asthma [PubMed PMID: 29949836] |
[7] | Hemler JA,Phillips EJ,Mallal SA,Kendall PL, The evolving story of human leukocyte antigen and the immunogenetics of peanut allergy. Annals of allergy, asthma [PubMed PMID: 26522257] |
[8] | Pinto LA,Stein RT,Kabesch M, Impact of genetics in childhood asthma. Jornal de pediatria. 2008 Aug; [PubMed PMID: 18690379] |
[9] | Weidinger S,Klopp N,Wagenpfeil S,Rümmler L,Schedel M,Kabesch M,Schäfer T,Darsow U,Jakob T,Behrendt H,Wichmann HE,Ring J,Illig T, Association of a STAT 6 haplotype with elevated serum IgE levels in a population based cohort of white adults. Journal of medical genetics. 2004 Sep; [PubMed PMID: 15342695] |
[10] | Barnes KC,Freidhoff LR,Nickel R,Chiu YF,Juo SH,Hizawa N,Naidu RP,Ehrlich E,Duffy DL,Schou C,Levett PN,Marsh DG,Beaty TH, Dense mapping of chromosome 12q13.12-q23.3 and linkage to asthma and atopy. The Journal of allergy and clinical immunology. 1999 Aug; [PubMed PMID: 10452776] |
[11] | Blumenthal MN, The role of genetics in the development of asthma and atopy. Current opinion in allergy and clinical immunology. 2005 Apr; [PubMed PMID: 15764904] |
[12] | Huang JL, Asthma severity and genetics in Taiwan. Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi. 2005 Jun; [PubMed PMID: 15986064] |
[13] | Sinclair R,Russell C,Kray G,Vesper S, Asthma Risk Associated with Indoor Mold Contamination in Hispanic Communities in Eastern Coachella Valley, California. Journal of environmental and public health. 2018; [PubMed PMID: 30410546] |
[14] | Jung S,Suh DI,Lee SY,Yoon J,Cho HJ,Kim YH,Yang SI,Kwon JW,Jang GC,Sun YH,Woo SI,Youn YS,Park KS,Cho HJ,Kook MH,Yi HR,Chung HL,Kim JH,Kim HY,Jung JA,Woo HO,Hong SJ, Prevalence, Risk Factors and Cutoff Values for Bronchial Hyperresponsiveness to Provocholine in 7-Year-Old Children. Allergy, asthma [PubMed PMID: 30088367] |
[15] | Sullivan PW,Vahram G,Abhishek K,Prakash N,Friedman HS,Benjamin O, Trends in Asthma Control, Treatment, Healthcare Utilization and Expenditures among Children in the United States by Place of Residence: 2003-2014. The journal of allergy and clinical immunology. In practice. 2019 Feb 14; [PubMed PMID: 30772478] |
[16] | Passalacqua G,Compalati E,Canonica GW, Investigational drugs for allergic rhinitis. Expert opinion on investigational drugs. 2010 Jan; [PubMed PMID: 20001557] |
[17] | Chiesa Fuxench ZC, Atopic Dermatitis: Disease Background and Risk Factors. Advances in experimental medicine and biology. 2017; [PubMed PMID: 29063427] |
[18] | Eckl-Dorna J,Villazala-Merino S,Linhart B,Karaulov AV,Zhernov Y,Khaitov M,Niederberger-Leppin V,Valenta R, Allergen-Specific Antibodies Regulate Secondary Allergen-Specific Immune Responses. Frontiers in immunology. 2018; [PubMed PMID: 30705676] |
[19] | Zugic V,Mujovic N,Hromis S,Jankovic J,Drvenica M,Perovic A,Kopitovic I,Ilic A,Nikolic D, Pattern of Response to Bronchial Challenge with Histamine in Patients with Non-Atopic Cough-Variant and Classic Asthma. Journal of clinical medicine. 2018 Jul 12; [PubMed PMID: 30002276] |
[20] | Byrne AL,Marais BJ,Mitnick CD,Garden FL,Lecca L,Contreras C,Yauri Y,Garcia F,Marks GB, Asthma and atopy prevalence are not reduced among former tuberculosis patients compared with controls in Lima, Peru. BMC pulmonary medicine. 2019 Feb 13; [PubMed PMID: 30760258] |
[21] | Resende SD,Magalhães FC,Rodrigues-Oliveira JL,Castro VN,Souza CSA,Oliveira EJ,Carneiro M,Geiger SM,Negrão-Corrêa DA, Modulation of Allergic Reactivity in Humans Is Dependent on {i}Schistosoma mansoni{/i} Parasite Burden, Low Levels of IL-33 or TNF-α and High Levels of IL-10 in Serum. Frontiers in immunology. 2018; [PubMed PMID: 30713536] |
[22] | Lloyd CM,Snelgrove RJ, Type 2 immunity: Expanding our view. Science immunology. 2018 Jul 6; [PubMed PMID: 29980619] |
[23] | Hon KL,Tsang KY,Kung JS,Leung TF,Lam CW,Wong CK, Clinical Signs, Staphylococcus and Atopic Eczema-Related Seromarkers. Molecules (Basel, Switzerland). 2017 Feb 14; [PubMed PMID: 28216598] |
[24] | Maciel-Guerra H,Penha MÁ,Jorge MFS,Libório RDS,Carrijo ACNDA,Parise-Fortes MR,Miot HA, Suppression of wheal and flare in histamine test by the main H1 antihistamines commercialized in Brazil. Anais brasileiros de dermatologia. 2018 Mar; [PubMed PMID: 29723372] |
[25] | Justiz Vaillant AA,Zito PM, Hypersensitivity Reactions, Immediate 2018 Jan; [PubMed PMID: 30020687] |
[26] | Chen X,Guan WJ,Sun SX,Zheng PY,Sun LH,Chen DH,Wang DD,Chen C,Sun BQ,Douglas Zhang XH, Effects of Intranasal Cellulose Powder on Asthma Control in Children With Mild-to-Moderate Perennial Allergic Rhinitis: A Randomized, Placebo-Controlled Trial. American journal of rhinology [PubMed PMID: 30704266] |
[27] | van der Schaft J,Thijs JL,Garritsen FM,Balak D,de Bruin-Weller MS, Towards personalized treatment in atopic dermatitis. Expert opinion on biological therapy. 2019 Feb 15; [PubMed PMID: 30768375] |
[28] | Braun C,Eigenmann P, [Management of childhood food allergies]. Revue medicale suisse. 2019 Feb 13; [PubMed PMID: 30763002] |
[29] | West CE, Probiotics for allergy prevention. Beneficial microbes. 2016; [PubMed PMID: 26689229] |
[30] | Baverel P,She D,Piper E,Ueda S,Yoshioka T,Faggioni R,Gevorkyan H, A randomized, placebo-controlled, single ascending-dose study to assess the safety, tolerability, pharmacokinetics, and immunogenicity of subcutaneous tralokinumab in Japanese healthy volunteers. Drug metabolism and pharmacokinetics. 2018 Jun; [PubMed PMID: 29622380] |
[31] | Bird JA,Sánchez-Borges M,Ansotegui IJ,Ebisawa M,Ortega Martell JA, Skin as an immune organ and clinical applications of skin-based immunotherapy. The World Allergy Organization journal. 2018; [PubMed PMID: 30555619] |
[32] | Yee CS,Rachid R, The Heterogeneity of Oral Immunotherapy Clinical Trials: Implications and Future Directions. Current allergy and asthma reports. 2016 Apr; [PubMed PMID: 26922433] |
[33] | Brand PL,Luz García-García M,Morison A,Vermeulen JH,Weber HC, Ciclesonide in wheezy preschool children with a positive asthma predictive index or atopy. Respiratory medicine. 2011 Nov; [PubMed PMID: 21839625] |
[34] | Martineau AR,Jolliffe DA,Greenberg L,Aloia JF,Bergman P,Dubnov-Raz G,Esposito S,Ganmaa D,Ginde AA,Goodall EC,Grant CC,Janssens W,Jensen ME,Kerley CP,Laaksi I,Manaseki-Holland S,Mauger D,Murdoch DR,Neale R,Rees JR,Simpson S,Stelmach I,Trilok Kumar G,Urashima M,Camargo CA,Griffiths CJ,Hooper RL, Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis. Health technology assessment (Winchester, England). 2019 Jan; [PubMed PMID: 30675873] |
[35] | Atanaskovic-Markovic M,Gomes E,Cernadas J,du Toit G,Kidon M,Kuyucu S,Mori F,Ponvert C,Terreehorst I,Caubet JC, Diagnosis and management of drug-induced anaphylaxis in children: an EAACI position paper. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2019 Feb 7; [PubMed PMID: 30734362] |
[36] | Dillman JR,Trout AT,Davenport MS, Allergic-like contrast media reaction management in children. Pediatric radiology. 2018 Nov; [PubMed PMID: 30242426] |
[37] | Bardash Y,Tham T,Olson C,Khaymovich J,Costantino P, Anaphylactoid hypersensitivity reaction from intra-arterial cetuximab: Clinical considerations and management. SAGE open medical case reports. 2019; [PubMed PMID: 30728973] |