Physicians’ Prescribing Behaviour and Clinical Practice Patterns for Allergic Rhinitis Management in Italy

Abstract

Background: Despite availability of clinical guidelines, underdiagnosis, undertreatment, and poor adherence are still significant concerns in allergic rhinitis (AR) therapeutic management. We investigated clinical practice patterns and prescribing behavior of Italian healthcare professionals (HCPs) specialized in AR management.

Methods: One-hundred allergologists, 100 ear, nose and throat (ENT) specialists, and 150 general practitioners (GPs) were recruited. The survey assessed: socio-demographic, work experience, monthly caseload, prescription drivers. Next, HCPs were invited to retrospectively recover patients’ clinical data to investigate: AR clinical characteristics, therapy management, prescription patterns, patient adherence. Descriptive statistics, Chi-square, One-Way analysis of variance, and Two-Way Analysis of Variance were performed.

Results: Allergologists visited more AR patients (31% of monthly caseload) than ENTs (21%, p<0.001), while GPs’ caseload was the lowest (6%). Clinical information of 2823 patients were retrieved of whom 1906 (67,5%) suffered from moderate/severe AR (discomfort score: 7,7±1,3) and 917 (32,4%) from mild AR (5.7±1.9). About one-third of mild patients had a discomfort score >=7. Main prescription drivers were “effective on all symptoms” (54,3% patients) and “quick symptom relief” (47,8%), whereas minor drivers were “affordable price” (13,4%) and “refundable” (8,7%). The most prescribed drugs were antihistamines and intranasal corticosteroids (79% and 55% prescriptions), followed by fixed-dose-combination of intranasal azelastine/fluticasone (19%). Polytherapy was the most common treatment strategy (59,6%). HCPs’ believe that the majority of the patients was adherent to treatment (88% with score>7).

Conclusions: This survey describes AR pharmacological management by Italian physicians. HCPs underestimated AR severity and had a non-realistic perception of patients’ adherence. These findings suggest that further efforts are required to improve AR clinical management in Italy.

Introduction

Allergic rhinitis (AR) is one of the most common diseases affecting adults worldwide with increasing incidence and prevalence in almost all western countries (1–5). Though it is not a serious condition, AR is widely accepted as a clinically relevant and disabling disorder accounting for a substantial burden of global morbidity (3,6) and a considerable economic impact (7–9). Indeed, patients with AR experience particularly bothersome symptoms which negatively affects everyday activities and quality of sleep, ultimately leading to reduced quality of life (QoL) (3,10–12) and to impaired work and school performance (9,13). In asthmatics subjects, coexistent AR exacerbates severity of asthma (14,15).  

Despite international and national are continuously reviewed and updated to optimize patient care guidelines (e.g. Allergic Rhinitis and its Impact on Asthma, ARIA) (16–19), AR clinical management is still unsatisfactory. and the rates of  underdiagnosis (12,20,21) and undertreatment (20–23) remain relevant. Inadequate control of symptoms not only is associated with delayed medical examinations and patient preference for over-the-counter drugs, but also it can cause serious diseases such as nasal polyp development, acute and chronic sinusitis, and otitis media (23,24). Patients’ low adherence to therapy is an additional factor affecting achievement of adequate symptom control (25–27).

In Italy, prevalence of AR has increased over the last 20 years from 16.8% to 25.8% (1,28,29). A survey by Spinozzi and coworkers showed that over half of the patients recruited by general practitioners (GPs) experience symptoms which significantly impairs their daily/social life (30). Strikingly, more than 25% of the interviewed subjects received no treatment despite the symptoms and 13.5% were inadequately treated. In addition, recent studies reported poor adherence to ARIA guidelines by Italian clinicians (31,32).

The present research investigated the current clinical practice patterns and prescribing behaviour of Italian healthcare professionals (HCPs) specialized in AR management. Allergologists, ear, nose and throat (ENT) specialists, and GPs were asked to retrospectively recover clinical data of real-life cases to assess: 1) prescribing behaviour based on patients’ characteristics; 2) AR therapeutic management; 3) opinions toward patients’ adherence.

Methods

Design, HCPs’ recruitment, and data collection

We carried out a survey among a total of 350 Italian HCPs treating patients suffering from AR.  The survey sample included 100 allergologists, 100 ENT specialists, and 150 GPs. HCPs were randomly selected from a national database. Exclusion criteria were: <5 years of clinical practice, <5 AR patients visited over the last month, participation to another market research in the previous 6 months. Recruitment was carried out via mail and it was planned to equally represent physicians from all Italian geographical macro-regions in each specialty area. The interviews were performed in April 2019 and data were collected through Computer Assisted Web Interviewing (CAWI) lasting 20 minutes.

The questionnaire used in the present research was designed based on findings from a systematic literature review and included two sections. The first section collected the HCPs’ socio-demographic data, such as age, gender, years of work experience, and number of monthly visited patients with AR. HCPs’ attitude toward relevant prescription drivers was likewise investigated (Appendix 1).

In the second section of the survey, HCPs were invited to retrospectively recover clinical information of the patients they visited over the last month. The information retrieved included patients’ demographics, disease characteristics (disease symptoms, presence of concomitant asthma) and symptoms-related discomfort experienced by patients and disease severity (Appendix 2). More specifically, HCPs were asked to allocate their patients into 2 classes of severity: 1) mild, when symptoms experienced by patients do not interrupt sleep or interfere with daytime activities; 2) moderate/severe, when symptoms cause significant difficulties with sleep and adversely affect daytime function (33). Thereafter, therapy management i.e. class of prescribed drugs, medication regimen, and follow-up intervals were investigated (Appendix 3). Medication regimes included: 1) monotherapy, when a single drug was used; 2) concomitant polytherapy, in which different drugs were simultaneously used; 3) sequential polytherapy, in which the use of a specific drug was sequential to the use of another drug (i.e. drugs given one after the other); 4) polytherapy, in which different drugs were used, some to be taken continuously and other to be taken as-needed. Next, prescription drivers based on patients’ characteristics (Appendix 4) were assessed. Physicians’ opinions about patient adherence to treatment was likewise explored (Appendix 5). Finally, HCPs’ perception of AR economic burden (i.e. patients’ absenteeism from work and reduced productivity) was evaluated (Appendix 6).  

Statistical analysis

Data were homogenously collected by means of a questionnaire including both multiple choice questions and Likert scale-based questions. A descriptive analysis was performed for all the evaluated variables, presenting the absolute frequencies in case of categorical variables and the mean with standard deviation in the case of the continuous variables. Mean ratings obtained from Likert-type scale-framed questions were used to investigate differences across study groups.

Differences in variable distributions across specialists were tested with Χ₂ chi-square/ or One Way analysis of variance (ANOVA) when appropriate. Kruskal-Wallis One Way Analysis of Variance on Ranks followed by Dunn's post hoc test were likewise used. Two Way ANOVA was used to investigate significance between specialty area and patient assignment to the different classes of AR severity. Tukey’s post hoc test was used for pairwise multicomparison procedure.

A p<0.05 was considered statistically significant. The data were analyzed using the statistics software SigmaPlot 11.0 (Systat Software, San Jose, CA, USA).

Results

Physicians’ sample characteristics and prescription drivers

Relevant characteristics of the 350 respondents are described in Table 1. With regard to AR caseload, allergologists visited more patients in the last month (a median of 40 patients, 31% of total caseload) than ENTs (21 patients, 21%) (p<0.001), while GPs’ caseload was the lowest (18 patients, 6% of caseload). About half of the patients seen by allergologists (45%) and ENTs (42%) received a new diagnosis of AR, whereas 80% of the AR patients visited by GPs were already diagnosed (p<0.001).

All the prescription drivers presented through the questionnaire (Appendix 1) were rated high by the interviewed clinicians (average scores were >7). Drivers with the highest score were “effective on all AR symptoms” (average score of the whole sample: 9.1±1.1) and “few/no side effects” (9.1±1.0). On the other hand, cost-related aspects were associated with the lowest scores in all the specialty groups and with smaller percentage of physicians endorsing the positive response options (i.e. score >9). For instance, only 36% of allergologists, 17% of ENTs, and 29% of GPs gave a positive answer to the item “refundable”.

Discussion

The present survey investigated the current clinical practice scenario of AR management in Italy. In addition to provide an extensive description of Italian HCPs’ prescribing behaviour, thes research discloses clinicians’ perspective about patients’ symptom discomfort and adherence.

AR is characterized by substantial medical and social burden with high use of healthcare resources worldwide (5,6,11,34) This disorder is associated with absenteeism from work, reduced productivity, and poor school performance (34,35). Recent studies indicate not only a global increase in the AR prevalence (3,6,36), but also high rates of underdiagnosis (3) and inadequate treatment (22).

In our survey, allergologist was the main reference specialist for the disease, followed by ENTs. GPs visited more cases suffering from mild AR compared to both allergologists and ENTs. Prescription attitude was similar between HCPs. Attributes related to medication efficacy, safety, and patient adherence were considered more relevant prescription drivers than ease of use and cost-related items.

Consistent with previous Italian studies (31,32), the most prescribed drugs were antihistamines and intranasal corticosteroids. A novel data disclosed by our survey is that allergologists and ENTs recommended fixed-dose combination intranasal Aze/flu to about 20% of the patients they visited. It is well-established that intranasal corticosteroids provide a more effective control of AR symptoms than antihistamines but their effect is relatively slow (hours) (18). Fixed-dose combination of intranasal fluticasone propionate and azelastine hydrochloride was shown to be more efficacious than intranasal corticosteroid monotherapy (37–42) and it offers the additional benefit of faster relief of symptoms (minutes) (39,40,43). This drug is also indicated when monotherapy with either intranasal antihistamines or corticosteroids do not adequately control the symptoms of AR (39,41,42,44). Of note, randomized clinical trials showed that fixed-dose formulation is more effective than loose combinations of corticosteroids and antihistamines in patients with moderate/severe seasonal AR (44). The newest ARIA guidelines based on both Grading of Recommendations Assessment, Development and Evaluation (GRADE) and real-world evidence (RWE) confirm and emphasize efficacy of fixed-dose combination of intranasal Aze/flu for both nasal and ocular symptom relief, adding this drug to first line therapies for AR patients (45). Of interest, our analysis showed that fixed-dose combination intranasal Aze/flu was used in both monotherapy and polytherapy regimens, with significant differences across clinicians. In fact, Aze/flu was preferentially used in monotherapy by ENTs, whereas it was more frequently recommended in polytherapy regimens by allergologists and GPs. This latter therapeutic strategy involved the simultaneous use of Aze/flu mainly together with antihistamines (ebastine, desloratine, bilastine). Assessing the risk of therapeutic duplication in patients suffering from AR is a crucial question that requires specific investigation.

Another remarkable finding of the present survey is that AR severity is underestimated by physicians, irrespective of the specialty area in which they operate. In fact, about half of the patients assigned to the mild class of severity actually experienced particularly bothersome symptoms. This observation is consistent with data reported by the European survey carried out in Germany, France, Italy, Spain, and UK, in which clinicians not only underestimated the severity of disease but also misdiagnosed the nature and discomfort of symptoms (12). As a correct classification of symptom frequency and severity is essential to select the best treatment option for each patient (13,18,46), an inaccurate patients’ allocation to severity categories can negatively impact AR therapy. The results provided by our analysis of AR pharmacological management according to patients’ severity further supports this concept. Indeed, patients assigned to moderate/severe AR were preferentially recommended a polytherapy-based approach rather than a monotherapy regimen. Based on this, we can speculate that some of the patients improperly assigned to the mild category were undertreated in our sample. AR undertreatment and inadequate management have been extensively documented (20–22), suggesting that this disease is still trivialized in some cases (3,22,23).

With regard to HCPs’ opinions about patient adherence, our investigation disclosed that clinicians believe all the patients will be compliant, even in the cases of severe AR.  This perception does not reflect the real scenario of patients’ adherence in the AR settings. In fact, it is widely accepted that adherence in AR patients is very low (25,26,47,48). A recent study, in which compliance was assessed in a real-life setting using a mobile phone App, confirmed that about 70% of the recruited European AR patients are non-adherent to medications (26). HCPs’ misperception of patient adherence in our sample is likely a consequence of low frequency of follow-up visits (once a year) and of lack of patients-clinicians communication (12,49).

According to the interviewed physicians, the main cause of low compliance was relief of AR symptoms, followed by cost-related issues. Lack of efficacy, adverse effects, treatment duration, and costs are generally associated with lower compliance (50). Patient satisfaction with treatment likewise appears to be a relevant factor in determining compliance, even if its contribution still needs to be elucidated. In fact, many researchers reported that dissatisfaction with treatment may cause non-adherence to therapy (51–53), whereas more recent studies revealed that patients discontinue their treatment when they felt better (47,54). In contrast to guidelines recommending the use of multiple drugs to achieve symptom control (45), recent data indicated that most patients experience poor symptom control with increasing medications (26,55). Hence, the use of single drug-based therapy could substantially ameliorate patient compliance. Finally, concerning drug cost, it is widely accepted that affordability of prescription medication has a role in therapy persistence (25). Of interest, clinicians recruited in our survey did not consider cost issues as relevant prescription drivers.

Conclusions

AR still represents a significant health problem because of the high burden of symptoms and impact on patients’ QoL. The various available clinical guidelines state that an accurate diagnosis, a thorough patient evaluation, and an adequate follow-up monitoring are a prerequisite to ensure optimal patient care.

The present research showed severity of AR symptoms is underestimated by Italian physicians, regardless of the specialty area in which they operate. This could lead to inadequate control of the disease. In addition, HCPs are not fully aware of the poor adherence to treatment.

These findings suggest that further efforts must be made to promote physicians’ adherence to clinical guidelines in order to improve AR management. Design of educational interventions for both GPs and specialists could improve characterization of the disease, help clinicians in the selection of the best treatment option, and promote a better patient-physician communication on the nature, severity, and impact of symptoms.

Abbreviations

AR, Allergic rhinitis

ARIA, Allergic Rhinitis and its Impact on Asthma

Aze/flu, azelastine/fluticasone

ENT, ear, nose and throat

GPs, general practitioners

GRADE, Grading of Recommendations Assessment, Development and Evaluation

HCPs, healthcare professionals

QoL, quality of life

RWE, real-world evidence

Declarations

Ethics approval and consent to participate

The present survey did not require ethics committees’ approval as no health intervention had been administered to participants (Italian law Decreto 8 febbraio 2013 n. 34).

The research was conducted by Doxa Pharma S.r.l.. in compliance with the General Data Protection Regulation (EU) 2016/679 (GDPR) and in line with well-established regulatory practices/procedures governing marketing research, including the Market Research Society (MRS) code of conduct (2019 revision) and the Italian Code of Professional Ethics (ASSIRM, 2016 revision).

Physicians actively chose to participate to the survey and signed the following documents: data retention policy, data privacy statement, and data processing agreement. The interview questions were not aimed at investigating sensitive issues like religious or political beliefs or sexual orientation. Doxa Pharma S.r.l  ensured pseudonymization of individual answers before primary data abstraction and analysis.

Consent for publication

All the authors gave consent to publication of the manuscript and, in case of its acceptance, the copyright is transferred to Clinical and Molecular Allergy.

Availability of data and materials

The findings of the survey are available from Doxa Pharma S.r.l.. However, these data were used under license and consequently they are not publicly available. Data are available from the authors upon reasonable request and with permission of Doxa Pharma S.r.l.

Competing interests

None to declare.

Funding

The survey was funded by Mylan N.V.

Author contribution

GP, AM, GS, JB, CF, and GWC designed the survey and interpreted the data; CL analyzed the data and wrote the manuscript. All authors reviewed and approved the final version of the manuscript.

Authors agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.

Acknowledgements

The authors thank Doxa Pharma S.r.l. for data collection and analysis.

References

1. De Marco R, Cappa V, Accordini S, Rava M, Antonicelli L, Bortolami O, et al. Trends in the prevalence of asthma and allergic rhinitis in Italy between 1991 and 2010. Eur Respir J. 2012;39(4):883–92.
2. Bjerg A, Ekerljung L, Middelveld R, Dahlén SE, Forsberg B, Franklin K, et al. Increased prevalence of symptoms of rhinitis but not of asthma between 1990 and 2008 in Swedish adults: Comparisons of the ECRHS and GA2LEN surveys. PLoS One. 2011;
3. Bauchau V, Durham SR. Prevalence and rate of diagnosis of allergic rhinitis in Europe. Eur Respir J. 2004;24(5):758–64.
4. Nathan RA, Meltzer EO, Selner JC, Storms W. Prevalence of allergic rhinitis in the United States. J Allergy Clin Immunol. 1997;
5. Schatz M. A survey of the burden of allergic rhinitis in the USA. Allergy Eur J Allergy Clin Immunol. 2007;62(SUPPL. 85):9–16.
6. Nathan RA. The burden of allergic rhinitis. Allergy Asthma Proc. 2007;
7. Zuberbier T, Lötvall J, Simoens S, Subramanian S V., Church MK. Economic burden of inadequate management of allergic diseases in the European Union: A GA 2 LEN review. Allergy Eur J Allergy Clin Immunol. 2014;69(10):1275–9.
8. Reed SD, Lee TA, McCrory DC. The economic burden of allergic rhinitis: A critical evaluation of the literature. PharmacoEconomics. 2004.
9. Stróżek J, Samoliński BK, Kłak A, Gawińska-Drużba E, Izdebski R, Krzych-Fałta E, et al. The indirect costs of allergic diseases. Int J Occup Med Environ Health. 2019;32(3):281–90.
10. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Review article Allergic Rhinitis and its Impact on Asthma ( ARIA ) 2008 * Review Group : Prim Care. 2008;63:8–160.
11. Valero A, Alonso J, Antépara I, Baró E, Colás C, Del Cuvillo A, et al. Health-related quality of life in allergic rhinitis: Comparing the short form ESPRINT-15 and MiniRQLQ questionnaires. Allergy Eur J Allergy Clin Immunol. 2007;62(12):1372–8.
12. G. W. Canonica JB, J. Mullol GKS, Virchow JC. A survey of the burden of allergic rhinitis in Europe. Allergy. 2007;62(Suppl. 85):17–25.
13. Seidman MD, Gurgel RK, Lin SY, Schwartz SR, Baroody FM, Bonner JR, et al. Allergic Rhinitis (Summary). Otolaryngol -- Head Neck Surg [Internet]. 2014; Available from: https://doi.org/10.1177/0194599814562166
14. Maio S, Baldacci S, Simoni M, Angino A, Martini F, Cerrai S, et al. Impact of asthma and comorbid allergic rhinitis on quality of life and control in patients of italian general practitioners. J Asthma. 2012;
15. Valovirta E, Pawankar R. Survey on the impact of comorbid allergic rhinitis in patients with asthma. BMC Pulmonary Medicine. 2006.
16. Hellings PW, Seys SF, Marien G, Agache I, Canonica W, Gevaert P, et al. ARIA masterclass 2018: From guidelines to real-life implementation. Rhinology. 2019.
17. Bousquet J, Bedbrook A, Czarlewski W, Onorato GL, Arnavielhe S, Laune D, et al. Guidance to 2018 good practice: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma. Clinical and Translational Allergy. 2019.
18. Brożek JL, Bousquet J, Agache I, Agarwal A, Bachert C, Bosnic-Anticevich S, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines—2016 revision. J Allergy Clin Immunol. 2017;140(4):950–8.
19. http://www.progetto-aria.it/aim.htm.
20. Esteban CA, Klein RB, Kopel SJ, McQuaid EL, Fritz GK, Seifer R, et al. Underdiagnosed and undertreated allergic rhinitis in urban school-aged children with asthma. Pediatr Allergy, Immunol Pulmonol. 2014;27(2):75–81.
21. Nolte H, Nepper-Christensen S, Backer V. Unawareness and undertreatment of asthma and allergic rhinitis in a general population. Respir Med. 2006;100(2):354–62.
22. Maurer M, Zuberbier T. Undertreatment of rhinitis symptoms in Europe: Findings from a cross-sectional questionnaire survey. Allergy Eur J Allergy Clin Immunol. 2007;62(9):1057–63.
23. Zuberbier T, Lötvall J, Simoens S, Subramanian S V., Church MK. Economic burden of inadequate management of allergic diseases in the European Union: A GA 2 LEN review. Allergy: European Journal of Allergy and Clinical Immunology. 2014.
24. Demoly P, Calderon MA, Casale T, Scadding G, Annesi-Maesano I, Braun JJ, et al. Assessment of disease control in allergic rhinitis. Clin Transl Allergy. 2013;3(1):1–7.
25. Baena-Cagnani CE, Canonica GW, Zaky Helal M, Gómez RM, Compalati E, Zernotti ME, et al. The international survey on the management of allergic rhinitis by physicians and patients (ISMAR). World Allergy Organ J. 2015;8(1):1–11.
26. Menditto E, Costa E, Midão L, Bosnic-Anticevich S, Novellino E, Bialek S, et al. Adherence to treatment in allergic rhinitis using mobile technology. The MASK Study. Clin Exp Allergy. 2019;(July 2018):442–60.
27. Bousquet J, Hellings PW, Agache I, Amat F, Annesi-Maesano I, Ansotegui IJ, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018): Change management in allergic rhinitis and asthma multimorbidity using mobile technology. J Allergy Clin Immunol. 2019;143(3):864–79.
28. Verlato G, Corsico A, Villani S, Cerveri I, Migliore E, Accordini S, et al. Is the prevalence of adult asthma and allergic rhinitis still increasing? Results of an Italian study. J Allergy Clin Immunol. 2003;
29. Serra G. Burden of allergic rhinitis in Italy : findings of the ARTE ** study. 2002;(8):43–53.
30. Spinozzi F, Murgia N, Baldacci S, Maio S, Pala AP, Casciari C, et al. Characteristics and predictors of allergic rhinitis undertreatment in primary care. Int J Immunopathol Pharmacol. 2016;29(1):129–36.
31. Canonica GW, Triggiani M, Senna GE. 360 degree perspective on allergic rhinitis management in Italy: A survey of GPs, pharmacists and patients. Clin Mol Allergy. 2015;13(1):1–8.
32. Maio S, Simoni M, Baldacci S, Angino A, Martini F, Cerrai S, et al. The ARGA study with Italian general practitioners: Prescriptions for allergic rhinitis and adherence to ARIA guidelines. Curr Med Res Opin. 2012;28(10):1743–51.
33. Lee CH, Jang JH, Lee HJ, Kim I-T, Chu MJ, Kim CD, et al. Clinical Characteristics of Allergic Rhinitis According to Allergic Rhinitis and Its Impact on Asthma Guidelines. Clin Exp Otorhinolaryngol. 2008;1(4):196.
34. Ozdoganoglu T, Songu M. The burden of allergic rhinitis and asthma. Ther Adv Respir Dis. 2012;6(1):11–23.
35. J. B., Marshall. Allergic diseases as a public health problem in Europe. Eur Allergy White Pap. 1997;
36. Asher M, Montefort S, Bjorksten B, Lai C, Strachan D, Weiland S, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood. Lancet. 2006;
37. Dykewicz MS, Wallace D V, Baroody F, Bernstein J, Craig T, Finegold I, et al. Treatment of seasonal allergic rhinitis An evidence-based focused 2017 guideline update. Ann Allergy, Asthma Immunol [Internet]. 2017; Available from: https://doi.org/10.1016/j.anai.2017.08.012
38. Meltzer E, Ratner P, Bachert C, Carr W, Berger W, Canonica GW, et al. Clinically relevant effect of a new intranasal therapy (MP29-02) in allergic rhinitis assessed by responder analysis. Int Arch Allergy Immunol. 2013;161(4):369–77.
39. Emeryk A, Emeryk-Maksymiuk J, Janeczek K. New guidelines for the treatment of seasonal allergic rhinitis. Postep Dermatologii i Alergol. 2019;36(3):255–60.
40. Bousquet J, Schünemann HJ, Hellings PW, Arnavielhe S, Bachert C, Bedbrook A, et al. MACVIA clinical decision algorithm in adolescents and adults with allergic rhinitis. J Allergy Clin Immunol. 2016;138(2):367-374.e2.
41. Carr W, Bernstein J, Lieberman P, Meltzer E, Bachert C, Price D, et al. A novel intranasal therapy of azelastine with fluticasone for the treatment of allergic rhinitis. J Allergy Clin Immunol. 2012;
42. Ratner P, Hampel F, Wheeler W, Sacks H. Efficacy of azelastine hydrochloride and fluticasone propionate combined in a single delivery device for treatment of ocular symptoms of seasonal allergic rhinitis. Ann Allergy, Asthma Immunol 2009 Annu Sci Meet Am Coll Allergy, Asthma Immunol ACAAI Miami, FL United StatesConference Start 20091105 Conf End 20091110Conference Publ. 2009;
43. Bousquet J, Meltzer EO, Couroux P, Koltun A, Kopietz F, Munzel U, et al. Onset of Action of the Fixed Combination Intranasal Azelastine-Fluticasone Propionate in an Allergen Exposure Chamber. J Allergy Clin Immunol Pract. 2018;
44. Hampel FC, Ratner PH, Van Bavel J, Amar NJ, Daftary P, Wheeler W, et al. Double-blind, placebo-controlled study of azelastine and fluticasone in a single nasal spray delivery device. Ann Allergy, Asthma Immunol. 2010;
45. Bousquet J, Schünemann HJ, Togias A, Bachert C, Erhola M, Hellings PW, 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. 2019;
46. Braido F, Arcadipane F, Marugo F, Hayashi M, Pawankar R. Allergic rhinitis: Current options and future perspectives. Current Opinion in Allergy and Clinical Immunology. 2014.
47. Bender BG. Motivating Patient Adherence to Allergic Rhinitis Treatments. Current Allergy and Asthma Reports. 2015.
48. Valovirta E DR. Patient Adherence to Allergic Rhinitis Treatment: Results From Patient Surveys. Medscape J Med. 2008;
49. Harrison E. The Cost of Not Taking Our Medicine: The Complex Causes and Effects of Low Medication Adherence. Am J Accountable Care. 2018;6(4):11–3.
50. Köberlein J, Kothe AC, Schaffert C. Determinants of patient compliance in allergic rhinoconjunctivitis. Curr Opin Allergy Clin Immunol. 2011;
51. Baiardini I, Braido F, Bonini M, Compalati E, Canonica GW. Why do doctors and patients not follow guidelines? Current Opinion in Allergy and Clinical Immunology. 2009.
52. Marple BF, Fornadley JA, Patel AA, Fineman SM, Fromer L, Krouse JH, et al. Keys to successful management of patients with allergic rhinitis: Focus on patient confidence, compliance, and satisfaction. Otolaryngol - Head Neck Surg. 2007;
53. Ciprandi G, Incorvaia C, Scurati S, Puccinelli P, Soffia S, Frati F, et al. Patient-related factors in rhinitis and asthma: The satisfaction with allergy treatment survey. Curr Med Res Opin. 2011;
54. Huang X, Matricardi PM. Allergy and Asthma Care in the Mobile Phone Era. Clinical Reviews in Allergy and Immunology. 2019.
55. Bédard A, Basagaña X, Anto JM1, Garcia-Aymerich J, Devillier P, Arnavielhe S, Bedbrook A, Onorato GL, Czarlewski W, Murray R, Almeida R7, Fonseca J, Costa E, Malva J, Morais-Almeida M, Pereira AM, Todo-Bom A, Menditto E, Stellato C BJM study group. Mobile technology offers novel insights into the control and treatment of allergic rhinitis: The MASK study. J Allergy Clin Immunol. 2019;144(1):135–43.