Revisiting Atopic March: Clinical Overview and Treatment Options

Allergies Develop in Clusters: Predictable Trajectories?

The concept of Atopic March has changed throughout time and is understood to be the progression of atopic dermatitis to other atopic conditions, including but not limited to asthma, allergic rhinitis, food allergy, and eosinophilic esophagitis in a nonlinear pattern. The atopic conditions stated above may be present in some cases or all of them. Also, the distinct trajectories of disease progression are likely reproducible and representative of the phenotypes observed in clinical practice. (1)

A recent study on Atopic March indicated that poly sensitization, atopic dermatitis persistence, parental atopy, early age of onset, and greater disease severity are the risk factor for atopic diseases. (1)

Atopic Disease: Indian Epidemiological Review

Atopic Dermatitis: First Manifestation of Atopic March (2): The prevalence of atopic dermatitis is wide-ranging (3.0–20.5%) globally. As per ISAAC study the prevalence rate of atopic dermatitis in India is about 5%. Food allergy is a known provoking cause of atopic dermatitis, and the prevalence of IgE-mediated food allergy is about 35% in children affected with atopic dermatitis. (3) The prevalence rate of food allergy in Indian children was 0.14 % as per the study, but a sensitization rate was relatively high (19.1%) to food allergens. (2)

Allergic Asthma and Allergic Rhinitis: End Progression of Atopic March (2): There are an estimated 37.9 million cases of asthma in India. The prevalence rate rose from 9% to 29.5% over a span of 20 years and was influenced by demographic changes. The prevalence of allergic rhinitis has gradually risen in India in the last two decades. Allergic rhinitis and asthma coexist in 70–80% of Indian patients, add the disease burden.

Early Diagnosis Vital for Atopic March

Given that allergic diseases occur in early life, appropriate treatment of allergies can prevent and alter the natural history of allergic diseases. Optimal treatment requires accurate determination of triggering allergens. (4) Early biomarkers of atopic susceptibility help target allergy and introduce preventive measures to high-risk infants, enabling early interventions to decrease allergic severity. (5) Focused treatment of allergic diseases in childhood might reduce the allergic disease burden in later life as a mechanism of atopic march underlies the clinical syndrome of another Atopic disease. (5)

Atopic March Management- Brief Overview: The similar mechanism of disease generation offers the possibility of rational treatments in atopic diseases. The main goal of the treatment is to interrupt the inflammatory cascade and inhibit the chemicals generated by an allergic reaction from the response on the epithelium. (6)

Antihistamines form the cornerstone of treatment for allergic disorders. (6) They improve allergic symptoms at sites other than the nose, such as the conjunctiva, palate, skin, and lower airways. (7) Leukotriene receptor antagonists play a role in various atopic diseases, as they exert their biological effects by binding to specific G-protein-coupled receptors. (8) Corticosteroids attenuate cytokine and chemokine release, reduce the mucosa's inflammatory cell infiltration, and play a vital role in atopic diseases. (6)

Antihistamines for the Management of Atopic March: Antihistamines inhibit sensorineural stimulation, vascular dilatation, vascular permeability, and smooth muscle contraction in nasal/lower airways, gastrointestinal axis, and within the skin. (9) Using first-generation antihistamines are considerably limited by side effects, mainly sedation. Second-generation antihistamines have been demonstrated to decrease allergy symptoms with less sedating effectively, and Fexofenadine is the least sedating. (7)

Why Fexofenadine? Clinical Evidence:

Allergic Rhinitis: A meta-analysis evaluated data from the metanalysis of double-blind, randomized controlled clinical trials to assess the efficacy and safety of Fexofenadine in allergic rhinitis. In 2664 patients receiving Fexofenadine (2662 placebo), a significant reduction of total symptoms scores (SMD −0.33; CI 95% −0.39 to −0.28 p < 0.00001) was found. Positive results were demonstrated for sneezing, rhinorrhea, itching, and congestion. No significant differences were reported in adverse events between active and placebo (OR 0.99; CI 95% 0.82 to 1.19 p= 0.90). Such evidence will encourage the consideration of Fexofenadine for treating allergic rhinitis. (10)

Allergic Wheal: In a recent study conducted in Brazil, ten healthy adults were subjected to the histamine test to compare the effect of the H1-antihistamines most used in the local clinical practice (including fexofenadine). Two hours after intake, all antihistamines, including fexofenadine, significantly reduced the wheal (p < 0.02) and the flare compared to the control. Fexofenadine 180 mg compared with desloratadine 5 mg significantly reduced histamine-induced flares (61% versus + 2%, respectively: p < 0.05) and wheals (p < 0.05) at 2 hours after treatment in adults and adolescents. (11)

Indian Evidence: An Indian study evaluated the efficacy of Fexofenadine in the Indian population (N=200) with allergic rhinitis and chronic urticaria. These patients have been treated with Fexofenadine 120mg once daily for allergic rhinitis and Fexofenadine 180mg for chronic urticaria for 7 days. The efficacy based on the medication effectiveness scale score noted the benefit from 3rd day by marking a moderate relief (symptoms noticeably improved) and a complete remission on 7th day (symptoms not present) in most patients. The findings noted that Fexofenadine is highly effective in the Indian population (p<0.001) suffering from allergic rhinitis and chronic urticaria. (12)

Dosage Regiment and Safety Profile Summary:

The recommended dose of Fexofenadine in adults is 60 mg PO BID or 180 mg PO daily. For children 2-12 years old: 30 mg PO BID; for children older than 12 years old: 60 mg PO BID or 180 mg PO daily. (13)

Fexofenadine is well-tolerated, and discontinuation due to adverse effects generally occurs in less than 5% of patients. (11)

Take-Home Message:

• Atopic march is the progression of atopic dermatitis and subsequent development of other atopic diseases, including asthma, allergic rhinitis, food allergy, and eosinophilic esophagitis.
• Allergic disorders are a major worldwide health concern, including in India.
• Since allergic diseases occur in early life, early recognition and intervention may reduce the Atopic march burden in later life.
• Antihistamines form the cornerstone of treatment for allergic disorders.
• Fexofenadine, a second-generation antihistamine, is effective and safe in treating various atopic disorders.

References:

1. Spergel JM, Du Toit G, Davis CM. Might biologics serve to interrupt the atopic march? [published online ahead of print, 2023 Jan 19]. J Allergy Clin Immunol. 2023;S0091-6749(23)00005-2. doi:10.1016/j.jaci.2023.01.001

2. Krishna MT, Mahesh PA, Vedanthan P, Moitra S, Mehta V, Christopher DJ. An appraisal of allergic disorders in India and an urgent call for action. World Allergy Organ J. 2020;13(7):100446. Published 2020 Aug 1. doi:10.1016/j.waojou.2020.100446

3. Bantz SK, Zhu Z, Zheng T. The Atopic March: Progression from Atopic Dermatitis to Allergic Rhinitis and Asthma. J Clin Cell Immunol. 2014;5(2):202. doi:10.4172/2155-9899.1000202

4. Douglass JA, O'Hehir RE. 1. Diagnosis, treatment and prevention of allergic disease: the basics. Med J Aust. 2006;185(4):228-233. doi:10.5694/j.1326-5377.2006.tb00539.x

5. Zainal NHM, Abas R, Mohamad Asri SF. Childhood Allergy Disease, Early Diagnosis, and the Potential of Salivary Protein Biomarkers. Mediators Inflamm. 2021;2021:9198249. Published 2021 Oct 8. doi:10.1155/2021/9198249

6. H Kim, J Bouchard, PM Renzi. The link between allergic rhinitis and asthma: A role for antileukotrienes? Can Respir J 2008;15(2):91-98.

7. Scadding GK, Kariyawasam HH, Scadding G, et al. BSACI guideline for the diagnosis and management of allergic and non-allergic rhinitis (Revised Edition 2017; First edition 2007). Clin Exp Allergy. 2017;47(7):856-889. doi:10.1111/cea.12953

8. Jo-Watanabe A, Okuno T, Yokomizo T. The Role of Leukotrienes as Potential Therapeutic Targets in Allergic Disorders. Int J Mol Sci. 2019;20(14):3580. Published 2019 Jul 22. doi:10.3390/ijms20143580

9. Jacques C, Floris I. How an Immune-Factor-Based Formulation of Micro-Immunotherapy Could Interfere with the Physiological Processes Involved in the Atopic March. Int J Mol Sci. 2023;24(2):1483. Published 2023 Jan 12. doi:10.3390/ijms24021483

10. Compalati E, Baena-Cagnani R, Penagos M, et al. al Efficacy and Safety Of Fexofenadine In Allergic Rhinitis (AR): A Metanalysis. Journal of Allergy and Clinical Immunology, The, 2009-02-01, Volume 123, Issue 2

11. Ansotegui, I.J., Bernstein, J.A., Canonica, G.W. et al. Insights into urticaria in pediatric and adult populations and its management with fexofenadine hydrochloride. Allergy Asthma Clin Immunol 18, 41 (2022). https://doi.org/10.1186/s13223-022-00677-z

12. Bikash Medhi. Efficacy of Fexofenadine in the Indian Population suffering from Allergic Rhinitis & Chronic Urticaria. 2006. JK Science. Vol. 8 No. 2, April-June

13. Craun KL, Schury MP. Fexofenadine. [Updated 2022 Dec 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK556104/