Geographical and socioeconomic differences in compliance with and access to allergen immunotherapy in Denmark: A nationwide registry-based study - 1998-2016.

BACKGROUND: Allergen immunotherapy (AIT) is a cost-effective treatment option in moderate-severe allergic rhino-conjunctivitis. Inequality in access to AIT and variation in compliance related to socioeconomic status or geographical location have not been described previously. OBJECTIVE: The aim of the study was to evaluate access to grass pollen AIT at various educational attainment levels in the five regions of Denmark. Furthermore, grass pollen AIT treatment compliance was evaluated with respect to age, educational attainment and geographical area. METHODS: The unique civil registration number of every citizen in Denmark was combined with the nationwide Danish National Health Service Prescription Database and Statistics Denmark Database to extract age, gender, residence and educational attainment of every citizen who collected prescribed AIT medication from 1998 to 2016. Then, compliance and use of AIT were calculated with respect to age, geographical location and educational attainment. RESULTS: The use of subcutaneous AIT (SCIT) was significantly higher in the Capital Region; this difference was less predominant for sublingual AIT (SLIT). People who were educated only to primary school or vocational training levels were less frequent users of AIT. Compliance was especially low in the Capital Region and among people educated only to primary school level. In the age groups, compliance was similar, apart from SLIT users aged 0-9, for whom compliance was higher. CONCLUSION: This nationwide study finds that SLIT has the potential to reduce inequality in access to AIT. A focus intervention is needed to facilitate access to and compliance with AIT in groups with lower socioeconomic status.

Use of allergen immunotherapy for treatment of allergic conjunctivitis.

PURPOSE OF REVIEW: The purpose of this article is to provide an overview of the literature pertaining to the use of allergen immunotherapy for treatment of allergic conjunctivitis with an emphasis on recent developments. RECENT FINDINGS: Both subcutaneous (SCIT) and sublingual (SLIT) immunotherapy continue to show efficacy in treating allergic conjunctival disease, subcutaneous more than sublingual. Adverse effects of sublingual therapy continue to be reported since the FDA's approval of SLIT tablets in 2014. Initial SLIT studies reported high rates of adherence, while real use reports identify rates of nonadherence/discontinuation ranging between 50 and 80%. Studies in polyallergic patients evaluating the efficacy of SLIT combination therapy report encouraging results. SUMMARY: Both SCIT and SLIT offers improvement in allergic conjunctival symptom scores and decrease medication utilization. Although SCIT has a higher likelihood of systemic reaction, SLIT has a very high rate of mild-to-moderate adverse events - especially in the first month. Cost-benefit analyses tend to favor SCIT (greater efficacy and less impacted by discontinuation rates).

Clinical assessment of tolerability, immunological and cutaneous reactivity effects of an abbreviated schedule with Olea europaeanative extract of subcutaneous immunotherapy.

Summary: Objectives. To evaluate the tolerability and efficacy of Olea europaea subcutaneous immunotherapy (SCIT) on patients with rhinoconjunctivitis. Methods. In this open clinical trial patients were assigned to an abbreviated build-up scheme. The outcomes were: number, percentage, and severity of adverse reactions. Secondary outcomes included: changes in immunoglobulin titers and changes in dose-response skin prick tests. Results. Only 8 systemic reactions were registered, which represented 7/47 (14.9%) of patients and 8/429 (1.9%) of administered doses. Regarding immunological parameters the significant increases of sIgG and sIgG4 evidenced the changes in the patient immune system. Cutaneous reactivity decreased significantly. Conclusions. Olea europaea SCIT (Allergovac® depot ROXALL Medicina España S.A.) showed a good safety and tolerability profile. Immunological changes with induction of blocking IgG and decreases in cutaneous reactivity were detected in the patients.

Utility elicitation in adults and children for allergic rhinoconjunctivitis and associated health states.

PURPOSE: Allergic rhinitis and asthma symptoms are detrimental to health-related quality of life (HRQoL). Health technology appraisal agencies often require cost-utility analysis when assessing new interventions. Appropriate utility estimates, which quantify the value of different conditions in cost-utility analyses, are scarce for allergic rhinitis and asthma health states. This study aimed to generate utilities for allergic rhinitis and asthma health states from a European general population sample of adults and children. METHODS: Health state descriptions incorporating symptoms, impact of symptoms on daily life and symptom treatment were developed using clinical guidelines. Descriptions were amended with clinician and patient input, and incorporated into a survey in which each health state was followed by a standard gamble (adults) or visual analogue scale (children) item. The survey was distributed to samples of adults and children aged 8 to 11 from four European countries that were stratified to represent the general population within that country. RESULTS: 1454 adults and 1082 children completed the survey. Mean health utilities ranged from 0.635 to 0.880 and those elicited in children were lower (0.635 to 0.705) than those elicited in adults (0.812 to 0.880). Disutilities assessing the impact of increased allergic rhinitis severity and comorbidities were also greater in children than in adults. CONCLUSIONS: Symptoms of allergic rhinitis and asthma were valued as having a clinically meaningful impact on HRQoL. Children valued health states as poorer than adults, and further research should investigate whether this reflects true preferential differences or results from methodological and/or comprehension differences between the two groups.

Does evidence support the use of cat allergen immunotherapy?

PURPOSE OF REVIEW: Cat allergy can manifest as allergic rhinitis, conjunctivitis and/or asthma. With widespread cat ownership and exposure, cat allergy has emerged as a major cause of morbidity. Cat allergen immunotherapy is a potential disease modifying treatment for patients with cat allergy. We examine evidence on the effectiveness, cost-effectiveness and safety of cat allergen immunotherapy and consider the clinical contexts in which it should be prescribed. RECENT FINDINGS: The European Association of Allergy and Clinical Immunology systematic reviews on allergic rhinitis and asthma along with the accompanying guidelines on allergic rhinitis were used as primary sources of evidence. Subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are most common routes of administration for allergen immunotherapy (AIT). A limited number of high-quality studies related to cat dander have shown mixed results in improvements in ocular and nasal symptoms, asthma symptoms, peak expiratory flow rate and medication use scores with subcutaneous immunotherapy. Two studies examining cat dander and cat-related allergy response with sublingual immunotherapy have shown mixed results in terms of symptomatic response. One randomized trial examining intralymphatic immunotherapy has shown a positive symptom response and a favourable safety profile. Although studies have reported mixed results regarding safety of SCIT, adverse events have been reported more commonly with SCIT than SLIT. SUMMARY: There is a limited body of high-quality evidence on the effectiveness and safety of cat AIT and no high-quality data on its cost-effectiveness. The available evidence on effectiveness is mixed based on studying a limited array of immunological, physiological and patient-reported outcome measures. Based on this evidence and extrapolating on the wider evidence base in AIT, it is likely that some patients may benefit from this modality of treatment, particularly those with moderate-to-severe disease who are inadequately controlled on allergen avoidance measures and pharmacotherapy and those who are monosensitized to Felix Domesticus 1. Further evidence is, however, required from larger trials before more definitive advice can be offered.

Findings from an Online Survey Assessing the Burden and Management of Seasonal Allergic Rhinoconjunctivitis in US Patients.

BACKGROUND: Seasonal allergic rhinoconjunctivitis (SARC) affects ≥16% of the US population annually. Telephone and in-office surveys have demonstrated negative effects of allergic rhinitis (AR) symptoms on sleep, daily activities, productivity, concentration, and emotions. OBJECTIVE: The objective of this study was to assess the patient-perceived burden of SARC in relation to newer treatments, increased access to treatments, and changing management protocols. METHODS: An online survey of symptom experience, impact on daily life, and management was conducted in US respondents who suffer (or whose child suffers) from SARC symptoms. RESULTS: A total of 1001 surveys were completed: 500 adults (≥18 years old) and 501 children (12-17 years old, documented by their parents). Similar to earlier AR surveys, SARC symptoms negatively affected the patient's (and family's) quality of life, and were most severe in the spring. Before being treated, >50% of respondents reported daily symptoms during their season; 75% to 80% considered their symptoms moderate to severe. Patients saw a variety of health care professionals (including pharmacists) and used over-the-counter and prescription medications for symptoms. Those using prescription medications were generally more satisfied with treatment and less likely to switch or discontinue treatment. Nasal and/or ocular symptoms drove adherence, seeing a health care professional, and reviewing and/or changing treatment. CONCLUSIONS: The majority of patients with SARC report moderate-to-severe symptoms that significantly impair their quality of life. However, patients appear to be taking more responsibility for their (child's) condition, and patient expectations for therapy are increasingly being met. Continued efforts will be needed to examine the contribution of better information and/or increased access to and availability of medications to control the disease.

Epidemiology of allergic conjunctivitis: clinical appearance and treatment patterns in a population-based study.

PURPOSE OF REVIEW: To analyse the most recently published studies on the prevalence of allergic conjunctivitis alone or in association with allergic rhinitis, and the clinical and demographic aspects of the disease. RECENT FINDINGS: Allergic conjunctivitis or conjunctival symptoms are present in 30-71% of patients with allergic rhinitis. Allergic conjunctivitis alone has been estimated in 6-30% of the general population and in up to 30% in children alone or in association with allergic rhinitis. Seasonal allergic conjunctivitis is the most frequent form; however, studies from tertiary, ophthalmology referral centers report that the chronic forms, such as vernal and atopic keratoconjunctivitis, are the most frequently seen by ophthalmologists. A recent large survey performed at a national level involving 304 ophthalmologists showed that the majority of patients with allergic conjunctivitis suffer annually of few episodes of mild ,intermittent conjunctivitis. However, 30% of patients are affected by frequent episodes with intense and persistent symptoms. Treatment is frequently not appropriate. SUMMARY: Even though allergic conjunctivitis is often associated to allergic rhinitis, epidemiology studies frequently do not include specific ophthalmological evaluations. An understanding of allergic conjunctivitis disease, its prevalence, demographics and treatment paradigms will provide important information towards understanding its pharmacoeconomics and burden on the national health systems.

Allergic conjunctivitis: a cross-sectional study.

BACKGROUND: Ocular allergy is a common disease in daily practice. OBJECTIVES: A cross-sectional study was conducted to evaluate clinical aspects of and therapeutic approaches to ocular allergy in Italy. METHODS: Of the 3685 patients affected by ocular allergy and enrolled by 304 ophthalmologists nationally, 3545 were eligible to be included in the statistical analysis. A questionnaire was administered in office to record demographic data, comorbidities, trigger factors, number of conjunctivitis episodes, and past treatments. Signs and symptoms were graded according to their severity, frequency, and duration. RESULTS: Mean age of enrolled patients was 38 ± 19 years. Seasonal allergic conjunctivitis (55% of patients) was equally distributed among the different age groups, while perennial allergic conjunctivitis (18%) increased with age and vernal keratoconjunctivitis (9%) was more frequent under the age of 18. Itching and redness were reported in 90% and 85%, respectively; lid skin involvement was observed in 22% of cases and keratitis in 11%. Pollen sensitivities were indicated as the most frequent triggers; however, exposure to non-specific environmental conditions, pollutants, and cigarette smoke was frequently reported. Only 35% of patients underwent a diagnostic evaluation of specific allergic sensitization, with positive allergy tests found in 82% of this subset. With regard to treatment, topical decongestants were used in 43% of patients, corticosteroids in 41%, antihistamines in 29%, systemic antihistamines in 27%, and mast cell stabilizers in 15%. CONCLUSION: This survey provided useful epidemiological information regarding the clinical characteristics and treatment options of a large cohort of patients affected by different forms of ocular allergy. CLINICAL RELEVANCE: An understanding of ocular allergic disease, its incidence, demographics, and treatment paradigms provides important information towards understanding its pharmacoeconomics and burden on the national health system.

Patient-reported outcomes and quality-of-life questionnaires in the assessment of rhinoconjunctivitis in childhood.

PURPOSE OF REVIEW: Rhinoconjunctivitis, and especially allergic rhinoconjunctivitis (ARC) are increasing in prevalence, progressively affecting the well being of more and more adults and children. Clinical trials using allergen immunotherapy (AIT), the sole causal treatment of allergies, are being conducted, but discussions on optimal patient-related outcomes (PROs) are still ongoing. RECENT FINDINGS: Almost all publications discussing PROs relate to adults. The authors comment on the importance of broader PROs when assessing the results of AIT trials, as focusing on only nasal symptom improvement and medication reduction does not capture the full benefit of AIT. Such intervention also improves comorbid allergic diseases and general well being. In studies on rhinoconjunctivitis in children, using medical treatment or immunotherapy published between November 2012 - February 2014 nasal symptom (and medication) scores were primary outcomes in 18 of 20 trials. Only two trials applied quality-of-life questionnaires. SUMMARY: Clinical trials conducted in children with ARC should be interpreted with caution, as most currently used PROs give a restricted view, by not considering disease manifestations beyond nasal/ocular symptoms. To correctly estimate the full benefit of AIT in pediatric patients with ARC, broader PROs should be investigated, including disease control and quality of health.

Assessment of a computerised decision support system for allergic rhino-conjunctivitis counselling in German pharmacy.

OBJECTIVE: In a prospective two-phase intervention study we evaluated a newly developed computerised pharmacy decision support system (PDSS) for the counselling of patients with allergic rhinitis and conjunctivitis. METHOD: Community pharmacists were invited to counsel a virtual patient in a first interview. Immediately thereafter, we trained pharmacists to operate the PDSS, which they applied in a second patient interview immediately following the training. We assessed the completeness of mandatory questions asked as defined by national guidelines. RESULTS: Participating pharmacists (n = 50, 78% female, mean age 34 [IQR: 27-40] years, 8 [2-14.5] years of practical experience, 32% specialised in community pharmacy) asked considerably more mandatory questions to confirm appropriateness of self-medication with 7 (5.25-9; 78%) from 9 questions compared to 2 (1-3; 22%) without PDSS (median; P < 0.001). In particular, using the PDSS more than doubled mandatory questions (9/12, 6.25-10; 75% vs. 4/12, 3-5; 33%; P < 0.001) relevant for appropriate drug selection. CONCLUSION: Pharmacists omitted many questions mandatory to assess whether self-medication is appropriate. Using the newly developed PDSS more than doubled the number of mandatory questions asked. The results suggest that the PDSS is ready for evaluation of its impact in real patients.

Assessment of clinical efficacy of CYT003-QbG10 in patients with allergic rhinoconjunctivitis: a phase IIb study.

BACKGROUND: Allergic symptoms are generally caused by exposure to substances to which people have become sensitized. Associated with this is an 'unbalanced' Th1/Th2 immune response with T cell responses skewed towards the production of Th2 cytokines, IL-4, 5, and 13 and high levels of IgE antibodies. Current immune modulating therapies require the use of allergens, carrying the risk to induce potentially severe allergic reactions. OBJECTIVE: Goal of the present study was to assess the safety and efficacy of an allergen-free immune modulator in patients suffering from perennial allergy. METHODS: In order to be protected from immediate degradation upon injection, a toll-like receptor 9 (TLR9) agonist was packaged into virus-like particles. These nanoparticles loaded with TLR9 ligands (CYT003-QbG10) were injected six times, at weekly intervals, into patients with house dust mite allergy in an attempt to ameliorate allergic symptoms by modifying the immune response towards allergens. Two different doses were compared against placebo in this double-blind, randomized phase IIb study (n=299). Public trial registry: http://clinicaltrials.gov (NCT00800332). RESULTS: The treatment was safe and generally well tolerated. Rhinoconjunctivitis symptoms were significantly lower in patients treated with high dose of CYT003-QbG10 as compared with placebo (scores 0.31 vs. 0.52, P=0.04) based on a standardized average combined symptom and medication score. Furthermore, patients in the high dose group reported a significantly better quality of life score post-treatment than patients on placebo (scores 0.71 vs. 1.21, P=0.02). The conjunctival provocation test revealed a median 10-fold increase in allergen tolerance in the high dose group while in the placebo group it remained unchanged. CONCLUSION AND CLINICAL RELEVANCE: Treatment with high-dose CYT003-QbG10 improved disease symptoms and reduced medication use in allergic individuals thus providing first evidence for a new potential immunotherapeutic.

Implementation of pre-seasonal sublingual immunotherapy with a five-grass pollen tablet during optimal dosage assessment.

BACKGROUND: The optimal dose (300IR) of a five-grass pollen sublingual immunotherapy tablet in terms of efficacy was previously demonstrated from the first pollen season. OBJECTIVE: Here, we aim to confirm whether this dose remained optimal during the peak of the pollen season by assessing the efficacy and quality of life data. METHODS: A total of 628 subjects with grass pollen rhinoconjunctivitis were randomized in a double-blind, placebo-controlled, multi-centre, pan-European trial. Subjects received once-daily tablets (Stallergenes, Antony, France) of 100IR, 300IR, 500IR or placebo, starting 4 months before and throughout the 2005 grass pollen season. The pollen season was defined as the first day of 3 consecutive days with a grass pollen count above 30 grains/m(3) of air, recorded using Hirst-type volumetric pollen traps, to the last day before 3 consecutive days with a pollen count below 30 grains/m(3). RESULTS: The grass pollen season lasted an average of 30 days, with a peak of 12 days. The mean treatment duration before the grass pollen season was similar in the four treatment groups (121.4+/-31.1 to 128.6+/-15.4 days in the safety population). Both the 300IR and 500IR groups had highly significant improvements in Rhinoconjunctivitis Total Symptom Score (RTSS) vs. placebo at the peak pollen season (P=0.0005 and 0.0014, respectively), which agreed with improvements in RTSS in the primary evaluations. The average RTSS scores were slightly elevated during the peak pollen season in all treatment groups. The overall Rhinoconjunctivitis Quality of Life Questionnaire score confirmed the optimal dosage 300IR at peak (P<0.0001) and at the end (P< or =0.0031) of the pollen season. All doses were well tolerated. CONCLUSION: At the peak pollen season, the efficacy and quality of life data for both 300IR and 500IR groups was significantly improved vs. the placebo group. These results confirm the conclusions of the primary evaluations and validate the use of 300IR tablets for clinical practice.

Assessment of combined symptom and medication scores for rhinoconjunctivitis immunotherapy clinical trials.

BACKGROUND: In randomized, double-blind, placebo-controlled clinical trials the efficacy of immunotherapy for allergic rhinoconjunctivitis is evaluated using the Average Rhinoconjunctivitis Total Symptom Score (ARTSS). Effective treatment is associated with lower ARTSS relative to placebo. For ethical reasons patients are provided with registered rescue medication, which may alleviate symptoms and thus reduce symptom scores. This effect biases the mean difference in ARTSS between effective treatment and placebo towards zero. Therefore, when rescue medication is taken by a patient, the ARTSS needs to be adjusted appropriately. METHODS: We considered five outcome measures: ARTSS, Average Rescue Medication Score (ARMS), and three combined symptom and RMSs. To assess the different outcome measures regarding their power to discriminate between effective treatment and placebo, we calculated their effect size when applied to data from a clinical trial of immunotherapy for allergic rhinoconjunctivitis. RESULTS: Of the five outcome measures considered, the average of the ARTSS and ARMS was associated with the largest effect size, and thus with the highest power to show treatment efficacy. Discriminant and multivariate analyses suggest that this average is approximately optimal among all weighted sums of ARTSS and ARMS. CONCLUSION: Our findings support recommendations made in a World Allergy Organisation document on methodological aspects of immunotherapy trials. The average of the ARTSS and ARMS should be considered as a primary efficacy variable in clinical trials of immunotherapy for allergic rhinoconjunctivitis.

Evaluation of visual analog scales for the assessment of symptom severity in allergic rhinoconjunctivitis.

BACKGROUND: The severity of rhinoconjunctivitis is typically monitored by means of nasal provocation tests (NPTs), where the nasally applied allergens trigger symptoms that are recorded using a scoring system. However, NPTs are time-consuming and stressful for patients; therefore, recording of symptoms during natural allergen exposure on visual analog scales (VASs) is increasingly being used in clinical trials. OBJECTIVES: To evaluate (1) the correlation between VAS symptom recording by patients during natural allergen exposure and symptom scoring by the physician during the NPT and (2) the possibility of replacing the more laborious and distressing allergen provocation tests with the more patient-friendly VAS. METHODS: A total of 119 patients with allergic rhinitis due to grass pollen were enrolled in the study between June 20, 2001, and January 31, 2002. Patients reported the severity of different seasonal symptoms on a VAS and underwent a NPT. RESULTS: No significant correlations between VAS and NPT scores were found. However, all the correlation coefficients between the symptom scores from the NPT and the corresponding symptom scores from the VAS were much higher for the female than the male subgroup. CONCLUSIONS: The VAS does not correlate with the NPT and, therefore, cannot replace the NPT. However, the result may suggest it worthwhile to explore the role of sex in the perception of allergy symptoms.

Quantitative assessment of the compliance with once-daily sublingual immunotherapy in children (EASY project: evaluation of a novel SLIT formulation during a year).

Compliance is a major determinant for allergy treatment, especially in children. Sublingual immunotherapy (SLIT) is self-managed at home, and no quantitative data on pediatric adherence are available. We studied the compliance in a large real-life setting. A simplified schedule of SLIT was used, consisting of a 10-day updosing phase followed by maintenance treatment in monodose containers to be taken daily (SLITOne). Italian specialists throughout Italy assessed the compliance in children who were newly prescribed SLIT according to guidelines. Parents were contacted with unscheduled telephone interviews at the third and sixth month of therapy and asked to count at that moment the remaining vials. Data from 71 children (38 boys, age range 2-13 yr) were enclosed in the database. Thirty had rhinoconjunctivitis, four asthma and 37 rhinoconjunctivitis + asthma. SLIT was prescribed for: mites in 57 (81%) subjects, grasses in 11 (15%) and 3 (4%) grass + olive mixture. Compliance data were available for all children at 3 months, and for 56 at 6 months. At 3 months, 85% of subjects had a compliance rate >75% (69% of them adhered >90%). At 6 months, 84% had a compliance rate >75% (66% of them adhered >90%). In four cases SLIT was discontinued for economical reasons, and in one case (1.4%) for side effects probably related to therapy. These data obtained in a quite large sample of children and in real-life confirm that the compliance with SLITOne is good, despite the therapy managed at home.

Patient dropouts before completion of optimal dose, multiple allergen immunotherapy.

BACKGROUND: Many patients don't complete the recommended 3 to 5-year course of immunotherapy. Why? OBJECTIVE: Determine the percentage of our patients receiving optimal dose, multiple-allergen immunotherapy from 1982 to 1996 who discontinued their immunotherapy prior to completion of the recommended 3 to 5-year immunotherapy protocol. Second, assess the reasons for these premature dropouts. Third, determine any differences related to the clinic location where injections are given. DESIGN AND METHODS: The medical records of patients who dropped out of our immunotherapy program before 3 years were analyzed by the author. SUMMARY OF RESULTS: Our dropout rate before 3 years was 12%. The five commonest reasons for early dropout were concurrent medical problems, noncompliance, change of residence, inconvenience, and allergic reactions. The systemic reaction rate for the 3-year dropout group was 1.00% compared with 0.9% for our overall study group. Eighty-eight percent of the systemic reactions were mild. About 1% of our immunotherapy patients quit early due to allergic reactions secondary to immunotherapy. CONCLUSIONS: The dropout rate for our optimal-dose patients is similar to/that reported previously by Tinkelman who apparently used a lower than optimal maintenance dose. (2) Many of our dropouts were predictable and avoidable. Few patients quit early due to allergic reactions secondary to our immunotherapy program.

Direct expenditures for the treatment of allergic rhinoconjunctivitis in 1996, including the contributions of related airway illnesses.

BACKGROUND: Previous estimates of the national economic burden of allergic rhinoconjunctivitis (AR/AC) have relied on data analyses in which AR/AC was the primary International Classification of Diseases-ninth revision-Clinical Modification (ICD-9-CM)-coded diagnosis. These studies ignore the costs when AR/AC was a secondary diagnosis to other disorders such as asthma and sinusitis. OBJECTIVE: We sought to determine the national direct cost of illness for AR/AC. METHODS: An expert panel used the Delphi technique to estimate the proportion of visits coded by other primary ICD-9-CM diagnoses in which AR/AC was a significant secondary comorbid condition. The costs of this proportion were deemed to be "attributable" to AR/AC and were added to the costs when allergic rhinitis and allergic conjunctivitis were the primary diagnoses. RESULTS: The cost when AR/AC was the primary diagnosis was $1.9 billion (in 1996 dollars). The cost when AR/AC was a secondary diagnosis was estimated at $4.0 billion, giving an estimate of $5.9 billion for the overall direct medical expenditures attributable to AR/AC. Outpatient services (63%, $3.7 billion), medications (25%, $1.5 billion), and inpatient services (12%, $0.7 billion) accounted for the expenditures. Children 12 years and younger accounted for $2.3 billion (38.0%). CONCLUSION: Upper airway allergy is an expensive disease process because of its readily apparent manifestations as AR/AC and its contribution to other airway disorders.