Evidence Report/Technology Assessment

Number 54

Prepared for:
Agency for Healthcare Research and Quality
Department of Health and Human Services
U.S. Public Health Service
2101 East Jefferson Street
Rockville, MD 20852

http://www.ahrq.gov/

Contract No. 290-97-0019

Prepared by:
New England Medical Center Evidence-based Practice Center
Aidan Long, M.D., Primary Technical Expert
Caroline McFadden, M.D., Assistant Project Director
Deirdre DeVine, M. Litt., Project Manager
Priscilla Chew, M.P.H., Research Associate
Bruce Kupelnick, B.A., Research Associate
Joseph Lau, M.D., EPC Project Director
Investigators

AHRQ Publication No. 02-E024

May 2002

This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. Endorsement by the Agency for Healthcare Research and Quality (AHRQ) or the U.S. Department of Health and Human Services (DHHS) of such derivative products may not be stated or implied.

AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and access. The information helps health care decisionmakers -- patients and clinicians, health system leaders, and policymakers -- make more informed decisions and improve the quality of health care services.

This document is in the public domain and may be used and reprinted without permission except for any copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders. AHRQ appreciates citation as to source, and the suggested format is provided below:

Long A, McFadden C, DeVine D, et al. Management of Allergic and Nonallergic Rhinitis (Evidence Report/Technology Assessment No. 54 (Prepared by New England Medical Center Evidence-based Practice Center under Contract No. 290-97-0019). AHRQ Pub. No. 02-E024. Rockville, MD: Agency for Healthcare Research and Quality. May 2002.

ISBN 1-58763-113-X
ISSN 1530-4396

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.

AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.

This report synthesizes the available evidence on the diagnosis of allergic and nonallergic rhinitis, the question of whether differentiating allergic from nonallergic rhinitis is important, the efficacy of treatments in nonallergic and allergic rhinitis, and how treatment of allergic rhinitis impacts the development of asthma or acute rhinosinusitis.

Primary research articles and meta-analyses evaluated for this report were identified through a Medline search of English language literature published between 1966 and October 2000.

We included cross-sectional and prospective studies evaluating diagnostic methods in allergic and nonallergic rhinitis. We used randomized controlled trials to evaluate the efficacy of treatments. We looked for prospective studies that evaluated the relationship between allergic rhinitis and later development of asthma or acute rhinosinusitis.

We reviewed 3,354 Medline titles, retrieved 228 articles, and included 88 randomized controlled trials and two prospective cohort studies in our report. Evidence tables of study features and results were produced for various treatment comparisons. Summary tables reported appraisal of the methodological quality of the studies, and summaries of their results.

No prospective study explicitly attempted to differentiate allergic from nonallergic rhinitis. The minimum level of testing necessary to confirm or exclude a diagnosis of allergic rhinitis has not been established in the literature.

Pharmaceutical companies supported the majority of the treatment trials. Thirteen randomized controlled trials assessed the efficacy of medications for treatment of nonallergic rhinitis symptoms. Only one study examined the role of antihistamines and three studies examined the efficacy of nasal corticosteroids. Oral decongestants are effective in controlling the symptom of nasal congestion and ipratropium bromide is beneficial in the management of rhinorrhea. There is little published evidence for use of antihistamines or nasal corticosteroids for the management of nonallergic rhinitis. Overall, these treatment modalities were well tolerated and devoid of major side effects.

There were 73 randomized controlled trials on the treatment of allergic rhinitis. The majority of studies show a clear benefit on the use of intranasal corticosteroids over either sedating or nonsedating antihistamines for relief of symptoms of nasal allergy. With respect to symptom alleviation in seasonal and perennial allergic rhinitis, study results indicate no consistent differences between sedating and nonsedating antihistamines, though the side-effect profile favors nonsedating antihistamines. No randomized controlled trials were identified that compared immunotherapy with antihistamines or with nasal corticosteroids in the treatment of seasonal and/or perennial allergic rhinitis. Studies provide strong support for the beneficial effect of cromoglycate in the management of both seasonal and perennial allergic rhinitis. A majority of studies reported no serious adverse events associated with the use of antihistamines, cromolyn, or intranasal corticosteroids.

Two prospective cohort studies demonstrate an increased likelihood of developing asthma over time in patients with allergic rhinitis, though no study was identified which addressed the question of whether treatment of allergic rhinitis can actually prevent the development of asthma. In addition, though the link between allergic rhinitis and rhinosinusitis is known, we identified no prospective studies on the outcomes of treated and untreated allergic rhinitis.

Beyond skin testing and diagnosis by exclusion, there is no literature on differentiating allergic from nonallergic rhinitis. The data concerning treatment of nonallergic rhinitis is scant and no single agent is identified as being uniformly effective in controlling all the symptoms associated with this condition. In allergic rhinitis treatment, nasal corticosteroids are superior to antihistamines and there is no consistent difference between sedating antihistamines and nonsedating antihistamines for the relief of nasal symptoms. The majority of studies reported no major adverse events associated with current treatments. There is insufficient evidence to address the relationship between allergic rhinitis and the development of asthma or rhinosinusitis.

Twenty to 40 million Americans are affected by allergic rhinitis, making it the sixth most prevalent chronic illness. The peak prevalence of allergic rhinitis is observed in children and young adults. Prevalence estimates range from 10 to 30 percent of adults and up to 40 percent of children, making allergic rhinitis currently the most common chronic condition found in children. Furthermore, in the past 30 years, there has been a dramatic increase in the prevalence of allergic rhinitis in "Westernized" societies; and studies from England, Sweden, and Australia have reported a doubling of prevalence over this time.

Allergic rhinitis is responsible for at least $1.8 billion annually for the direct cost of physician visits and medication expenses, or nearly 2.5 percent of the $47 billion annual direct cost for respiratory treatment in the United States. Moreover, the estimated value of lost productivity to employers and society resulting from allergic rhinitis approaches nearly $3.8 billion annually. In the mid-1990s the resulting total annual cost for allergic rhinitis amounted to $5.6 billion.

Rhinitis, in which the classification by etiology may be allergic or nonallergic, is a disorder characterized by inflammation of the mucous membranes lining the nasal passages. The symptoms of allergic rhinitis, which can be difficult to accurately distinguish from those of vasomotor rhinitis, typically include sneezing, nasal itch, rhinorrhea, nasal obstruction, post-nasal drip and occasionally nasal pain. Based on timing or periodicity of symptoms, allergic rhinitis may be classified as either seasonal or perennial.

The symptoms of allergic rhinitis result from exposure to allergens in a susceptible (sensitized) individual. Allergens include pollen, grass, weed, and house-dust mite etc., and symptoms are triggered by the interaction of an allergen with immunoglobulin E (IgE) molecules which bind through the high affinity IgE receptor to the surface of mast cells in the nasal mucosa or to circulating basophils. Recognition of the allergen by the IgE antibody leads to activation of the mast cell or basophil, causing the release of a variety of mediators, including histamine and leukotrienes, which in turn attract inflammatory cells from the peripheral circulation. This orchestrated chain of events results in the characteristic clinical features of allergic rhinitis.

Nonallergic rhinitis is characterized by sporadic or persistent perennial nasal symptoms that do not result from IgE-mediated immunopathologic events. The symptoms can be similar to allergic rhinitis, but with a less prominent nasal itch and conjunctival irritation. The distinction between allergic and nonallergic rhinitis can be difficult to distinguish clinically, but the distinction may be important for prognosis and treatment decisions.

This evidence report on the management of allergic rhinitis is based on a systematic review of the literature. The American Academy of Family Physicians served as the science partner on this report. The American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology also provided technical experts to work with the staff of the Evidence-based Practice Center (EPC). Through a series of teleconferences, this panel of experts worked to identify specific issues and refine key questions central to this report, and they nominated peer reviewers who were not involved in the synthesis of evidence or in the writing of this report. The EPC then conducted a comprehensive search of the medical literature to identify studies addressing the key questions specified by the panel on the management of allergic rhinitis and nonallergic rhinitis.

With input from the science partners, the following questions were formulated:

Question 1. How does one diagnose allergic and nonallergic rhinitis (especially vasomotor)?

1.1 What differentiates allergic from nonallergic rhinitis with respect to symptoms, signs, physical examination, and diagnostic testing?

1.2 What is the minimum level of testing necessary to differentiate allergic from nonallergic rhinitis?

Question 2. Is differentiating allergic from nonallergic rhinitis important?

2.1 Are treatments different?

2.2 Are outcomes different?

Question 3. How does one treat nonallergic and allergic rhinitis?

3.1 For nonallergic rhinitis:

1. What is the efficacy of antihistamines (all classes), nasal corticosteroids, sympathomimetics, leukotriene modifiers, anticholinergics, or cromoglycate compared with placebo?
2. What are the side effects due to antihistamines, nasal corticosteroids, sympathomimetics, leukotriene modifiers, anticholinergics, or cromoglycate?

3.2 For allergic rhinitis:

1. What is the efficacy of antihistamines versus nasal corticosteroids, antihistamines versus immunotherapy (desensitization), nasal corticosteroids versus immunotherapy, sedating versus nonsedating antihistamines, other agents (cromolyn, leukotriene modifiers, sympathomimetics, ipratropium).
2. What are the side effects/adverse events due to antihistamines, nasal corticosteroids, sympathomimetics, or leukotriene modifiers?

3.3 Do efficacy and side effects of treatment vary by severity of rhinitis or patient characteristics?

Question 4. How does treatment of allergic rhinitis impact on the development of asthma?

4.1. What is the likelihood of developing asthma with untreated allergic rhinitis (natural history)?

4.2. How does treatment of allergic rhinitis affect the likelihood of developing asthma?

4.3. How does treatment of allergic rhinitis affect the likelihood of developing bacterial sinusitis?

Studies for the literature review were identified primarily through a MEDLINE search of English language literature published between 1966 and October 2000. We also consulted technical experts and examined references of published meta-analyses and selected review articles to identify additional studies. Articles that met the inclusion criteria were incorporated in our evidence report.

For this evidence report, the EPC compiled evidence tables of study features and results, appraised the study methods, and summarized results. If published meta-analyses were available on specific treatment topics, we assessed the effects of treatments evaluated in these reports.

The MEDLINE search yielded 3,354 titles. We screened the titles and abstracts of these citations and retrieved 228 full-length articles for further examination. Reports published only as abstracts in proceedings were rejected from further consideration. Specific inclusion criteria were developed for each of the key questions. For questions 1 and 2, we included all cross-sectional and prospective studies evaluating diagnostic methods in allergic and nonallergic rhinitis including, but not limited to, allergen skin testing, serum IgE measurements, nasal provocation challenge, nasal rhinomanometry and nasal biopsy. For question 3, we included randomized controlled trials of the following interventions in allergic rhinitis: antihistamines versus nasal corticosteroids, antihistamines versus immunotherapy, nasal corticosteroids versus immunotherapy, sedating versus nonsedating antihistamines, cromolyn sodium, anticholinergic agents, leukotriene modifers and sympathomimetics. In the treatment of nonallergic rhinitis we included randomized controlled trials of antihistamines, nasal corticosteroids, sympathomimetic agents, leukotriene modifers, anticholinergics and cromoglycate. For question 4, we included prospective studies evaluating the relationship between allergic rhinitis and subsequent development of asthma or bacterial sinusitis.

The evidence-grading scheme we used assessed four dimensions that are important for the interpretation of the evidence:

• study size
• applicability
• summary of efficacy and safety outcomes
• methodological quality

The evidence we found for the management of allergic and nonallergic rhinitis is summarized in two complementary forms: first, the evidence tables provide detailed information on key features of study design and results of all the studies reviewed; second, a narrative and tabular summary of the strength and quality of the evidence of each study is provided for each comparison.

In addition to the conclusions described in this summary, we believe that the data support the following observations:

• Most of the clinical trials were supported by pharmaceutical companies.
• There were no studies that addressed the specific question of practical clinical interest: Is differentiating allergic rhinitis from nonallergic rhinitis important? Are treatments or outcomes different? Differentiation of allergic from nonallergic rhinitis is important if treatments are significantly different and if the outcomes of treatment including prevention of complications differ in response to those treatments. However, similar treatments are frequently employed in the two conditions.
• There were few trials in nonallergic rhinitis and their size was generally small. Thirteen trials conducted between 1982 and 1999 enrolled about 450 patients. In several comparisons of interest, there were only 20 to 30 patients in the trials. There were no studies that examined the efficacy of leukotriene modifiers. There were only two randomized controlled trials, with a total of 90 patients, that examined the role of oral decongestants in the relief of symptoms of nasal congestion.
• The trials were heterogeneous with respect to inclusion criteria, dosage regimens, study duration and reporting of results.
• The lack of reporting of data on variability of the outcome estimates made it difficult, if not impossible, to perform meta-analysis.
• Although almost all the studies we analyzed were randomized controlled trials, many did not meet high standards for methodological quality.
• There were no specific studies of the pediatric population. Even though some studies may have enrolled patients in pediatric ranges, separate data were not reported for this subgroup. Therefore, no specific conclusions could be drawn for the pediatric population.

• We found no studies that specifically sought to differentiate between allergic and nonallergic rhinitis on the basis of clinical symptoms, signs on physical examination, or the presence or absence of comorbid conditions.
• The minimum level of testing necessary to confirm or exclude a diagnosis of allergic rhinitis has not been established in the literature. There were no studies addressing the question of minimum level of diagnostic testing necessary to differentiate between allergic and nonallergic rhinitis that met the criteria described in the methods section of this report.
• No diagnostic test has been specifically developed to diagnose nonallergic rhinitis.
• Given the absence of studies to differentiate nonallergic rhinitis, diagnostic testing rather than symptoms or signs is necessary to differentiate isolated vasomotor or nonallergic rhinitis from allergic rhinitis. Only one small recent study suggests that total serum IgE may be as useful as specific allergy skin prick tests which, in turn, are more useful than radioallergosorbent testing (RAST) in confirming a diagnosis of allergic rhinitis.

• Antihistamines (all classes) versus placebo: Only one study which examined the role of antihistamines in the treatment of nonallergic rhinitis met the inclusion criteria. However, because the antihistamine used an ingredient in an antihistamine-decongestant combination product, the outcomes related to the antihistamine component of this drug cannot be separately identified. The Food and Drug Administration (FDA) recently approved a nasal topical product - azelastine (an H1 antihistamine) for the treatment of vasomotor rhinitis.
• Nasal corticosteroids: Two of three identified studies employed budesonide and the other used beclomethasone. One study indicated that the symptoms of nasal congestion were improved by budesonide without alteration in other symptoms of nonallergic rhinitis. In the other two studies, comparison was made between the nasal corticosteroid and nasal ipratropium bromide. One study favored the nasal corticosteroid but the other failed to differentiate between the two interventions on the basis of symptom relief. Intranasal corticosteroids have been recommended for long term therapy in nonallergic rhinitis and the two are approved by the FDA.
• Sympathomimetics versus placebo: Only two randomized controlled studies were identified which examined the role of oral decongestants (phenylpropolamine) in treatment of nonallergic rhinitis. In both studies emphasis was placed on relief of symptoms of nasal congestion. However, the FDA has urged companies marketing phenylpropanolamine to voluntarily withdraw the drug from the market while the FDA initiated regulatory actions to mandate such withdrawals. The only currently available orally active decongestant, pseudoephedrine, was not identified in any clinical trial concerning management of nonallergic rhinitis.
• Leukotriene modifiers versus placebo: No studies were identified looking at the efficacy of leukotriene modifiers in the treatment of nonallergic rhinitis.
• Anticholinergics versus placebo: Each of these five trials studied intranasal ipratropium bromide and each study demonstrated the efficacy of ipratropium in reducing nose blowing frequency and rhinorrhea.
• Cromoglycate versus placebo:Two randomized controlled trials identified as looking at the effects of cromoglycate in nonallergic rhinitis recorded improvement in symptoms of rhinitis with active treatment compared to placebo.
• Side effects/adverse effects: There were no side effects or adverse events reported in the studies of antihistamines or nasal corticosteroids. There is a report on the suppressive effect of belcomethasone nasal spray on bone growth in children and all nasal steroid preparations in the United States now warn of this adverse event. In the two studies comparing cromoglycate, there were no significant adverse effects associated with its use. In only one of the two studies involving sympathomimetics were adverse events such as drowsiness, nausea and headache described. Significant side effects of nasal dryness and nasal irritation were recorded in three of the five studies looking at ipratropium.

• Antihistamines vs. nasal corticosteroids: One published systematic review reported that for six individual nasal symptoms studied, as well as for overall nasal symptoms, nasal corticosteroids produced significantly greater relief than did oral antihistamines. Our search identified eight new studies that were not included in this meta-analysis. Seven of the studies favored intranasal corticosteroids over antihistamines both in respect to improvement in global nasal symptoms as well as in most individual nasal symptoms. One study showed better symptom improvement with cetirizine alone over fluticasone alone. Thus, the overwhelming majority of studies clearly favor the use of intranasal corticosteroids over either sedating or nonsedating antihistamines for relief of symptoms of nasal allergy. These results are true for both seasonal allergic rhinitis and perennial allergic rhinitis.
• Antihistamines vs. immunotherapy: No randomized controlled trials were identified directly comparing immunotherapy with antihistamines in the treatment of seasonal and/or perennial allergic rhinitis. Immunotherapy is generally considered as a long-term disease-modifying treatment measure requiring months to years of treatment, whereas antihistamines are most often used for immediate symptom relief. Therefore, direct comparisons with respect to effectiveness/efficacy are not likely to be undertaken.
• Nasal corticosteroids versus immunotherapy: No randomized controlled trials were identified which directly compared immunotherapy with intranasal corticosteroids in the treatment of seasonal and/or perennial allergic rhinitis.
• Sedating versus nonsedating antihistamines: With respect to symptom alleviation in seasonal and perennial allergic rhinitis, study results indicate no consistent benefit of sedating antihistamines over nonsedating antihistamines. However, the side-effect profile favors use of nonsedating antihistamines.
• Other agents (cromolyn, leukotriene modifiers, sympathomimetics, ipratropium): Studies provide strong support for the beneficial effect of cromoglycate in the management of both seasonal and perennial allergic rhinitis. Two clinical trials were identified which looked at the effects of decongestant drugs in allergic rhinitis and suggest some benefit in relief of nasal congestion but not other symptoms. The trial of ipratropium showed no significant differences between dosages of ipratropium but there was significant reduction in rhinorrhea and postnasal drip.
• Side effects/adverse events: A majority of the studies reported no major adverse events associated with the use of antihistamines. In those studies where major adverse events were reported, somnolence, dry mouth, dizziness and headache were identified most frequently. These symptoms were seen almost exclusively with the sedating antihistamines. Epistaxis, headache and pharyngitis were the most frequently reported side effects of nasal corticosteroids. None of the studies reported systemic side effects from intranasal corticosteroids in the short-term treatment studies. There is a report on the suppressive effect of belcomethasone nasal spray on bone growth in children and all nasal steroid preparations in the United States now warn of this adverse event. No major adverse events were reported in studies of cromolyn; among the minor reported side effects were high frequency of nasal irritation, headache and nasal congestion.

We found no data to address this question. There were no studies that categorized patients by disease severity or concurrent disease while addressing either efficacy or safety.

Studies addressing the temporal relationship between onset of rhinitis symptoms and onset of asthma symptoms have revealed that a significant proportion of patients experience rhinitis symptoms in advance of the development of clinical symptoms of asthma. Two prospective cohort studies have been published which show an increased likelihood of patients with allergic rhinitis developing asthma over time.

No study was identified which addressed the question of whether treatment of allergic rhinitis can actually prevent the development of asthma. The data, however, suggest a mechanistic linkage between these two diseases and the ability of nasal corticosteroids in treating allergic rhinitis to impact certain characteristics of asthma (e.g. seasonal increase in bronchial hyper-responsiveness).

The link between allergic rhinitis and rhinosinusitis is known. Cross-sectional studies have shown an increased prevalence of acute and chronic bacterial sinusitis among allergic rhinitis patients. Similarly, there is an increased prevalence of atopy and allergic rhinitis among patients with chronic bacterial sinusitis. However, in order to determine the effect of treatment of allergic rhinitis on the development of bacterial sinusitis, data from prospective studies on the outcomes of treated and untreated allergic rhinitis are needed. We identified no such studies meeting these criteria.

More research on key clinical questions in allergic and nonallergic rhinitis should be funded by nonproprietorial sources. Almost every trial that reported funding sources was funded by a pharmaceutical company. These trials usually address issues of the drug of one company versus the drug of another company. Thus, important questions about optimal clinical management of patients are often not addressed or relevant clinical information is unavailable.

Better assessment of allergic and nonallergic rhinitis is required. The minimum amount of diagnostic testing required to differentiate between these two conditions remains uncertain. Research should be conducted to determine the type and panel size of inhalant aeroallergen skin testing and on RAST. Research on whether recommendation/implementation of standard measures to minimize exposure to indoor aeroallergens, such as house-dust mites, pet allergens and cockroaches, might be cost effective in the management of chronic rhinitis. Further research should be conducted to determine the effects of minimizing exposure to allergens, even in the absence of differentiation between allergic and nonallergic rhinitis and even without determining a patient's precise allergic sensitivities.

Additional studies are needed to address other specific questions:

• The role of antihistamines for symptom relief in nonallergic rhinitis.
• The role of nasal corticosteroids in nonallergic rhinitis. If it can be rigorously documented that nasal corticosteroids are helpful to treat nonallergic rhinitis, the need to differentiate from nonallergic rhinitis may be lessened.
• The role of antihistamines in nonallergic rhinitis with eosinophilia syndrome (NARES).
• The role of cromoglycate use in nonallergic rhinitis.
• The role of allergen avoidance in patients with allergic rhinitis. Would this approach obviate the need for diagnostic testing in a substantial proportion of patients?
• The efficacy of a myriad of complementary therapies now being employed in the treatment of nonallergic rhinitis.
• Whether interventions for allergic rhinitis have preventive effects on asthma.

Higher quality studies and more studies for multiple but standardized research variables are needed. Standards for clinical trials in allergic and nonallergic rhinitis must adhere to those for clinical trials in general. After the FDA approval of a drug, additional high-quality trials of rhinitis relief are still needed to understand the optimal use of the drug in specific populations and settings. The trials should enroll greater numbers of patients for longer intervals than has generally been true in the past; apply blinding and "active" placebos when appropriate or uniform control treatments otherwise; and employ adequate between-arm washout intervals, and assess side-effects.

A major limitation of the data identified in this analysis is the heterogeneity of inclusion and exclusion criteria, diagnostic tests, outcome measures, and circumstances of testing found in the randomized controlled trials. This situation makes synthesizing the research results confusing and difficult. Reducing this heterogeneity by implementing a set of standard research variables would greatly assist when comparing studies. The characteristics of patients enrolled in studies also need to be clearly defined. This is critical to ensure internal validity and to allow for study comparisons, data analyses, and in the application of the results to clinical practice. Standardization of research variables would also aid in identifying the best strategies for identifying patients with allergic or nonallergic rhinitis.