Allergen immunotherapy is the only disease-modifying treatment option for allergic rhinitis, with
adherence being its major limitation. We report a case of an adolescent with rhinitis, proven allergy to
multiple non-homologous pollens, and troublesome symptoms despite maximal symptomatic therapy during
the late spring and early summer months. Allergen immunotherapy to the most clinically relevant allergen
was initiated under the supervision of a pediatrician. Shortly before her second year of treatment, she
transferred to adult care and maintained a high degree of adherence and a favourable response to
immunotherapy. In conclusion, allergen immunotherapy is effective in polyallergic adolescents with good
adherence

Marković, Ivan

Vukičević Lazarević, Vesna

Šola, Ana Marija

English

Allergen immunotherapy is the only disease-modifying treatment option for allergic rhinitis, with

adherence being its major limitation. We report a case of an adolescent with rhinitis, proven allergy to

multiple non-homologous pollens, and troublesome symptoms despite maximal symptomatic therapy during

the late spring and early summer months. Allergen immunotherapy to the most clinically relevant allergen

was initiated under the supervision of a pediatrician. Shortly before her second year of treatment, she

transferred to adult care and maintained a high degree of adherence and a favourable response to

immunotherapy. In conclusion, allergen immunotherapy is effective in polyallergic adolescents with good

adherence

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Professional paper  Stručni članak     ISSN 1848-817X Coden: MEJAD6 52 (2022) 3  201      Allergen immunotherapy in the polyallergic adolescent  Alergen imunoterapija u polialergičnog adolescenta  Vesna Vukičević Lazarević, Ana Marija Šola, Ivan Marković*  Summary   Allergen immunotherapy is the only disease-modifying treatment option for allergic rhinitis, with adherence being its major limitation. We report a case of an adolescent with rhinitis, proven allergy to multiple non-homologous pollens, and troublesome symptoms despite maximal symptomatic therapy during the late spring and early summer months. Allergen immunotherapy to the most clinically relevant allergen was initiated under the supervision of a pediatrician. Shortly before her second year of treatment, she transferred to adult care and maintained a high degree of adherence and a favourable response to immunotherapy. In conclusion, allergen immunotherapy is effective in polyallergic adolescents with good adherence. Key words: allergen immunotherapy, rhinitis, adolescents, therapy adherence   Sažetak  Alergenska imunoterapija je jedina terapijska opcija alergijskog rinitisa koja modificira tijek bolesti, a glavno ograničenje je terapijska adherencija.  U ovom radu prikazujemo slučaj adolescentice s rinitisom i dokazanom  alergijom na višestruke nehomologne peludi sa simptomima koji su joj ometali svakodnevni život unatoč maksimalnoj simptomatskoj terapiji tijekom kasnog proljeća i ranog ljeta. Alergenska imunoterapija na klinički najrelevantniji alergen započeta je pod nadzorom pedijatra, a neposredno prije druge godine liječenja bolesnica je prešla u skrb interniste. Unatoč prelasku u adultnu skrb, održana je adherencija liječenja i pratio  se povoljan odgovor na imunoterapiju. Zaključno, alergenska imunoterapija je učinkovita u polialergičnih adolescenata s dobrom terapijskom adherencijom. Ključne riječi: alergenska imunoterapija, rinitis, adolescenti, adherencija za terapiju   Background  Allergic rhinitis is the most prevalent immunological disorder1, which impairs people's quality of life2 and imposes considerable economic expenses.3 The British Society of Allergy and Clinical Immunology (BSACI) guidelines advocate a progressive approach to pharmacotherapy dependent on the severity of the disease.4 Patients with moderate-severe persistent allergic rhinitis who do not respond to maximal symptomatic treatment  should be considered for allergen immunotherapy.4,5 Unfortunately, compliance with allergen immunotherapy, particularly sublingual immuno-therapy, is challenging across all age groups.6 Adherence to therapy is particularly problematic in adolescents and young adults (AYA), a subgroup of patients aged 11 to 25 who have been recognised to lack self-management skills7, resulting in poor compliance.8 The pandemic of COVID-19 (Coronavirus disease 2019) has only exacerbated the problem. A recent European Academy of Allergy  *Specijalna bolnica za plućne bolesti, Rockefellerova 3, Zagreb (Vesna Vukičević Lazarević, dr.med.; Ana Marija Šola, dr.med.; Ivan Marković, dr.med.)  Correspondence address / Adresa za dopisivanje: Vesna Vukičević Lazarević, Specijalna bolnica za plućne bolesti, Rockefellerova 3, 10 000 Zagreb E-mail: vesna.vukicevic.lazarevic@pulmologija.hr Primljeno/Received 2022-08-19; Ispravljeno/Revised 2022-09-30; Prihvaćeno/Accepted 2022-10-07 Med Jad 2022;52(3):201-206  Vukičević Lazarević V et al. Allergen immunotherapy in the polyallergic adolescent – Med Jad 2022;52(3):201-206  202  and Clinical Allergy (EAACI) survey revealed widespread undertreatment with allergen immunotherapy across all age categories since the pandemic began, owing to limited healthcare resources.9 This case report aims to present successful allergen immunotherapy with good adherence to therapy in a polyallergic AYA during a pandemic.  Case presentation   An adolescent Caucasian female patient presented to her paediatrician with symptoms consistent with late spring rhinitis (with the highest peak of symptoms in May and June), including itching, sneezing, nasal obstruction and discharge. The symptoms persisted for more than four days per week and more than four weeks, impairing sleep and daily activities as measured by a Visual Analogue Scale (VAS) rating of more than 5. According to Allergic Rhinitis and its Impact on Asthma (ARIA) criteria, rhinitis was classified as moderate-severe persistent.10,11 She experienced similar symptoms in early spring and early autumn, but with duration shorter than four days a week, and four consecutive weeks, with no impairment of sleep, daily activities, or school, and a VAS score under 5, which ARIA classifies as mild intermittent rhinitis.10,11 The patient reported no lower respiratory tract disease symptoms or pollen food syndrome. She had mild atopic dermatitis as an infant, which was resolved by her second year of life. She attended high school and shared an apartment with her family that was well-ventilated and free of moulds and pets. The family history was positive for atopy. The patient was an exceptionally self-confident clarinet player. Unfortunately, her clarinet performance was significantly hindered by her rhinitis symptoms, which made her upset. Otherwise, she had no psychological or other medical issues.  Investigation  The patient presented with mildly wet eyes, allergy shine, nasal blockage, and anterior rhinoscopy revealed a pale hypertrophic nasal mucosa and inferior turbinates with a clear nasal discharge. Allergy test results, a complete blood count, C-Reactive Protein, immunoglobin profile, and cytologic examination of the upper respiratory tract are listed in Table 1. The test results showed the sensitisation to grass, trees, ragweed, and cats. Because there was no correlation between symptoms and cat exposure, the allergy test results to cat dander were interpreted as merely indicative of sensitivity rather than a clinically significant allergy. Pollen allergies were clinically significant, with grass pollen causing the most troublesome symptoms. Nasal allergen challenges to prove the allergies to pollens and exclude allergy to cat dander were not performed. Pulmonary function tests were in reference values with the negative bronchodilatory test, and fractional exhaled nitric oxide was 26 ppb. Other tests recommended by BSACI guidelines4 were not performed because there was no clinical need based on the patient's history and examination findings.  Differential diagnosis  Rhinitis is defined as the presence of at least two of the following symptoms: itching/sneezing, nasal discharge, and obstruction for more than one hour on most days.12 The aetiology of rhinitis can be allergic, non-allergic, infectious, or a combination of these.4 Allergic rhinitis in regions with a four-season climate, can be classified as seasonal caused by a variety of outdoor allergens (particularly pollens) and perennial caused by year-round indoor allergens (dust mites, moulds, cockroaches, and animal dander).10 Furthermore, local allergic rhinitis, a subtype of allergic rhinitis, is defined by the absence of a positive skin prick test and specific immunoglobulin E in the presence of a positive nasal allergen challenge.13 Non-allergic rhinitis can be idiopathic, eosinophilic, autonomic, drug, hormonal or food-induced and atrophic rhinitis or part of a systemic disorder.4 Our patient was diagnosed with seasonal allergic rhinitis to grass, tree, and ragweed based on the history and clinical findings.  Treatment  The patient was treated with an oral antihistamine, intranasal corticosteroid spray, and allergy avoidance according to BSACI guidelines4, but symptoms remained moderate-severe persistent throughout the late spring, with a VAS greater than 5. Step-up with an intranasal spray containing a combination of corticosteroid and antihistamine was trialled with partially successful, but VAS remained greater than 5. The patient was under the care of a paediatrician in a secondary care hospital for two years. Conversation with her and her parents were held to evaluate her self-care and disease management abilities. The official evaluation suggested by the  Vukičević Lazarević V et al. Allergen immunotherapy in the polyallergic adolescent  – Med Jad 2022;52(3):201-206  203 Table 1. Results of initial diagnostic tests. Tablica 1. Rezultati inicijalnih dijagnostičkih ispitivanja  Skin prick test (mm) Kožni prick test IgE in serum (kIU L-1) specific to IgE u serumu (kIU L-1) specifičan na Blood count Krvna slika Positive control Pozitivna kontrola 6.0 Cat dander Epitel mačke  1.21 White blood count (×109 L-1) Bijela krvna slika 6.4 Negative control Negativna kontrola 0.0 Dactylis glomerata >100.0 Eosinophils (Dunger) 150.0 Grass pollen Pelud trava 15.0 Betula verrucosa 3.16 Haemoglobin (g L-1) 131.0 Tree pollen Peluda stabala 6.0 Corylus avellana 0.67 Platelets (×109 L-1) 293.0 Ambrosia  Ragweed  Artemisiifolia pollen Pelud artemisiifolia 7.0 Ambrosia artemisiifolia 5.47 Mean corpuscular volume (fL) Srednji korpuskularni volumen 90.2 House dust mite Kućna grinja 0.0 Cockroach Žohar  0.0 Mean corpuscular hemoglobin (pg) Srednji korpuskularni hemoglobin 30.2 Immunoglobin profile (gL-1) Profil imunoglobina Cytology (%) Citologija  Biochemistry (mg L-1) Biokemija  IgA 1.8 Sputum eosinophil proportion Udio eozinofila u sputumu 5.0 C-Reactive Protein C-reaktivni protein IgM 1.9 Nasal brush eosinophil proportion Udio eozinofila u brisu nosa četkicom 15.0  IgG 13.5     EAACI guidelines through a questionnaire (such as “ready, steady, go”) was not carried out.7 She was offered by her paediatrican a trial of allergy immunotherapy to grass, the allergen that caused her the most distressing symptoms, because she was highly motivated and compliant with the therapy but only had partial success with the standard treatment. The patient chose pre seasonal sublingual immunotherapy drops for three sequential years because of availability on the market, short therapy duration, and reduced healthcare visits. Allergen immunotherapy consisted of titration and maintenance phase, and two vials with different concentrations of allergens. One vial contained 10IR/ml (one pressure = 1 IR), and the other one contained 300IR/ml (one pressure = 30 IR) of allergen. After the first dose of titration phase was administered in the secondary care hospital under the supervision of a paediatrician with no immediate adverse effects, the second dose and all subsequent doses were administered at home. During this phase of treatment, she developed symptoms of itchy ears and small bumps under the tongue half an hour after sublingual immunotherapy, which were treated with oral antihistamines. On day 12, she reached the maintenance phase, which consisted of four pressures of the second vial (300 IR/ml). She responded well to allergen immunotherapy, with a symptom reduction greater than 50% during the first late spring season.  Follow-up  The second year of allergen immunotherapy was complicated by the pandemic and the need to transfer to an adult physician because the patient had turned eighteen. The transfer was accomplished by email conversation between the patient, paediatrician and adult physician. Additionally, the transition report written by the paediatrician, allowed the adult physician to continue treatment with minimal in-person contact. The first dose of the Vukičević Lazarević V et al. Allergen immunotherapy in the polyallergic adolescent – Med Jad 2022;52(3):201-206  204 second year of allergen immunotherapy was administered under the supervision of an adult physician in our secondary care hospital at the first in-person visit. She performed pre-and post-treatment peak flow measurements and was discharged to home therapy after a half-hour. The third year of therapy began in early January 2022. Responses to different therapy options measured by VAS are shown in Figure 1.    Figure 1. Timeline of therapeutic intervention and outcomes on symptoms of allergic rhinitis as measured by visual analogue scale (VAS). Slika 1. Vremenski raspored terapijske intervencije i ishoda simptoma alergijskog rinitisa mjereno vizualnom analognom ljestvicom (VAS).    Discussion  Allergen immunotherapy, the administration of high doses of allergens in steadily increasing amounts, is the only disease-modifying treatment of allergic rhinitis. As a result of receiving immunotherapy at high doses, the dendritic cells in the body create cytokines that alter the immune response from Th2 to Th1 and trigger Tregs proliferation and the creation of IgA, IgG, and IgG4 blocking antibodies in Breg cells.14 Allergen immunotherapy can be administered sublingually or subcutaneously. According to EAACI Guidelines on Allergen Immunotherapy, both monoallergic and polyallergic patients can be treated.5,15 Despite the current guidelines, unfortunately, many allergists are still reluctant to administer allergen immunotherapy to polyallergic patients.  However, allergen immunotherapy can be highly successful if the most clinically relevant allergen is used for treatment.16 Sublingual immunotherapy is safe and effective for patients with allergic rhinitis caused by grass pollen with no reported deaths and local reactions that can be treated with oral H1-antihistamines.4, 17-19 The type of allergen immunotherapy used in this patient was carefully selected based on the patient's history, and it was extremely effective. However, adolescents such as our patient may be incapable of self-management, resulting in insufficient treatment adherence and other adverse outcomes.20 Additionally, as adolescents reach the age of eighteen, they are compelled to move from paediatric to adult medical care resulting in feelings of loss and fear of the unknown21, as well as missed appointments and inadequate management of allergic diseases.22 Due to that, EAACI developed guidelines for the effective transition of AYA in Vukičević Lazarević V et al. Allergen immunotherapy in the polyallergic adolescent  – Med Jad 2022;52(3):201-206  205 2020, outlining the importance of initiating transfer preparation early enough for the patient to be emotionally prepared.7 Transitioning entails acquiring accurate knowledge about the condition in order to avoid exacerbations and sustain disease control through multi-systemic approach, patient activation measures, transition readiness assessment tools (e.g. ready, steady, go questionnaires) and regular meetings between paediatric and adult health care providers.7 However, due to the Covid pandemic restrictions on in-person health care management, strict adherence to EAACI guidelines on effective AYA transition was not possible in this instance. Nevertheless, an online interaction between patient, paediatrician and adult physician revealed that the patient was mature and strongly motivated for treatment. Despite the multiple challenges associated with such a young age and pandemic, adherence was outstanding in our case, most likely due to the patient motivation and treatment efficacy and simplicity. This case demonstrates that allergen immunotherapy to single allergen is effective in polyallergic patients even during pandemic-related constrains in health care services in adolescents infamous for their lack of adherence.  Conclusions  • Allergen immunotherapy is the only disease-modifying treatment of allergic rhinitis. • Allergen immunotherapy using a single allergen is successful in polyallergic patients. • Adolescents can have good adherence to allergen immunotherapy. • Sublingual immunotherapy is a good option for allergen immunotherapy during a pandemic. • Online communication during the pandemic was very useful for patient management and transitioning patients from paediatric to adult care  References  1. Bauchau V, Durham SR. Prevalence and rate of diagnosis of allergic rhinitis in Europe. Eur Respir J 2004; 24: 758-764. 2. Laforest L, Bousquet J, Pietri G et al. Quality of life during pollen season in patients with seasonal allergic rhinitis with or without asthma. International archives of allergy and immunology. 2005; 136: 281–286.  3. Blaiss MS. Cognitive, social, and economic costs of allergic rhinitis. Allergy Asthma Proc 2000; 21: 7–13. Available from DOI: 10.2500/108854100778248953 4.  Scadding GK, Kariyawasam HH, Scadding K 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;47:856-889.  5. Roberts G, Pfaar O, Akdis CA et al. EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis. Allergy 2018;73:765-798.  6. Cox LS, Hankin C, Lockey R. Allergy immunotherapy adherence and delivery route: location does not matter. J Allergy Clin Immunol Pract 2014; 2, 156–160.  7. Roberts G, Ortiz- Vazquez M, Knibb R et al. EAACI guidelines on the effective transition of adolescents and young adults with allergy and asthma. Allergy. 2020; 75: 2734-2752. 8. Rhodes BJ. Patient dropouts before completion of optimal dose, multiple allergen immunotherapy. Annals  Allergy Asthma Immunol 1999;82:281–286.  9. Pfaar O, Agache I, Bonini M et al. COVID-19 pandemic and allergen immunotherapy-an EAACI survey. Allergy. 2021; 76: 3504–3516.  10. Bousquet J, van Cauwenberge P, Khaltaev N. Allergic Rhinitis and Its Impact on Asthma. J Allergy Clin Immunol 2001; 108(5 Suppl): S147-S334. 11. Bousquet J, Schünemann HJ, Togias A et al. Next-generation Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines for allergic rhinitis based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) and real-world evidence. J  Allergy Clin Immunol 2020; 145: 70-80.e3. 12. Greiner AN, Hellings PW, Rotiroti G, Scadding GK. Allergic rhinitis. Lancet. 2011;378:2112-2122.  13. Rondón C, Campo P, Togias A, Fokkens WJ, Durham SR, Powe DG,  et al.  Local allergic rhinitis: concept, pathophysiology, and management. J Allergy Clin Immunol 2012;129: 1460–1467.  14. Shamji MH, Durham SR. Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers. J Allergy Clin Immunol 2017; 140: 1485-1498.  15. Bousquet Jho, Pfaar O, Agache I et al. ARIA‐EAACI care pathways for allergen immunotherapy in respiratory allergy. Clin Trans Allergy 2021; 11: e12014. 16. Demoly P, Passalacqua G, Pfaar O, Sastre J, Wahn U. Managementof the polyallergic patient with allergy immunotherapy: a practice-based approach. Allergy Asthma Clin Immunol 2016;12:2.  17. Radulovic S, Calderon MA, Wilson D, Durham S. Sublingual immunotherapy for allergic rhinitis. The Vukičević Lazarević V et al. Allergen immunotherapy in the polyallergic adolescent – Med Jad 2022;52(3):201-206  206 Cochrane database of systematic reviews. 2010; (12):CD002893.  18. Panzner P, Petras M, Sykora T, Lesna I. Double-blind, placebo-controlled evaluation of grass pollen-specific immunotherapy with oral drops administered sublingually or supralingually. Respir Med 2008;102:1296-1304.  19. Ott H, Sieber J, Brehler R et al. Efficacy of grass pollen sublingual immunotherapy for three consecutive seasons and after cessation of treatment: the ECRIT study. Allergy. 2009;64:179-86. 20. Grootens-Wiegers P, Hein IM, van den Broek JM, de Vries MC. Medical decision-making in children and adolescents: developmental and neuroscientific aspects. BMC Pediatr 2017; 17:120.  21. Blakemore SJ, Robbins, TW. Decision-making in the adolescent brain. Nat Neurosci. 2012; 15: 1184–1191.  22. Backer V, Bornemann M, Knudsen D, Ommen H. Scheduled asthma management in general practice generally improve asthma control in those who attend. Respir Med. 2012;106:635-641. Available from: doi:10.1016/j.rmed.2012.01.005).  

Allergen immunotherapy in the polyallergic adolescent

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