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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.
| Carolyn M. Clancy, M.D. | Robert Graham, M.D., Director |
| Acting Director | Center for Practice and |
| Agency for Healthcare Research | Technology Assessment |
| and Quality | Agency for Healthcare Research |
| and Quality |
| The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service. |
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:
What is the efficacy of antihistamines (all classes), nasal corticosteroids, sympathomimetics, leukotriene modifiers, anticholinergics, or cromoglycate compared with placebo?
What are the side effects due to antihistamines, nasal corticosteroids, sympathomimetics, leukotriene modifiers, anticholinergics, or cromoglycate?
3.2 For allergic rhinitis:
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).
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.
This report summarizes the scientific evidence for diagnosing and treating allergic and nonallergic rhinitis. This topic was selected by the Agency for Healthcare Research and Quality in response to a request from the American Academy of Family Physicians. The report provides summaries of evidence for use by different groups, including primary care practitioners, specialists, researchers, policy decision makers, and health care financiers. Recognizing the different interests and approaches of these groups, this report focuses on the diagnosis and treatment of allergic and nonallergic rhinitis in the primary care, clinical practice setting. We sought evidence on diagnostic methods that can help differentiate between allergic from nonallergic rhinitis. We summarize the evidence on the efficacy of treatments for these conditions.
Twenty to forty million Americans are affected by allergic rhinitis (Dykewicz, Fineman, Skoner, et al., 1998) making it the sixth most prevalent chronic illness (Collins, 1997). The peak prevalence of allergic rhinitis is observed in children and young adults. Estimates range from 10 to 30 percent of adults and up to 40 percent of children suffer with this condition, making allergic rhinitis currently the most common chronic condition found in children (Fireman, 2000). 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 confirmed a doubling of prevalence over this time (Aberg, 1989; Aberg, Hesselmar, Aberg, et al., 1995; Hopper, Jenkins, Carlin, et al., 1995).
Despite the high prevalence of the disease, there is still insufficient epidemiologic data. Population surveys frequently have relied on physician-diagnosed rhinitis for primary data, which might underestimate the true prevalence of rhinitis (Aberg, 1989; Aberg, Hesselmar, Aberg, et al., 1995; Fleming and Crombie, 1987; Hopper, Jenkins, Carlin, et al., 1995). While population studies have been regularly performed by directly administered questionnaires, followed by telephone contact, which probably provide more accurate information, this approach probably still underrates the true prevalence of disease (Dykewicz, Fineman, Skoner, et al., 1998). In addition, most epidemiological studies have been directed towards estimating the prevalence of seasonal rhinitis because perennial allergies are more difficult to identify since its symptom complex overlaps with chronic sinusitis, recurrent upper respiratory infections, and vasomotor rhinitis (Dykewicz, Fineman, Skoner, et al., 1998).
Rhinitis encompasses a group of disorders affecting the mucous membranes lining the nasal passages. Typical symptoms of rhinitis include sneezing episodes, nasal itching, rhinorrhea, nasal obstruction, postnasal dripping and occasionally nasal pain. Based on timing or periodicity of symptoms, allergic rhinitis may be classified as either seasonal or perennial. Rhinitis is also classified under etiology as either allergic or nonallergic (Ng, Warlow, Chrishanthan, et al., 2000).
The symptoms of allergic rhinitis result from exposure to allergens in a susceptible (sensitized) individual (Kay, 2001). Allergens include pollen, grass, tree, weed, house-dust mite etc., and symptoms are triggered by the interaction of an allergen with IgE molecules bound, through the high affinity IgE receptor, to the surface of mast cells in the nasal mucosa or circulating basophils. Recognition of the allergen by the IgE antibody leads to activation of the mast cell or basophil causing the release of preformed granule-associated mediators (including histamine), membrane derived lipid mediators (including leukotrienes), as well as cytokines and chemokines which are responsible for attracting inflammatory cells from the peripheral circulation to the site of degranulation. This orchestrated chain of events results in the characteristic clinical features of allergic rhinitis (Fireman, 2000; Kay, 2001). Clinically, allergic rhinitis may be associated with "early phase" symptoms occurring within minutes of allergen exposure (due to the release of preformed mediators) and "late phase" symptoms, seen at 4-8 hours after exposure due to synthesis of newly formed mediators and infiltration of inflammatory white blood cells from the circulation (Bellanti and Wallerstedt, 2000; Skoner, 2001). Nasal itching is a prominent symptom during the early phase; sneezing, congestion and rhinorrhea are seen in both early and late phases, but nasal congestion dominates the late phase reaction.
Genetic factors probably play an important role in the development of allergic rhinitis (Fireman, 2000). It has been suggested that if both parents are atopic, chances of allergic disease risk in the offspring are 50 percent or higher, a number that increases to 72 percent if parents are afflicted with the same atopic disease (Fireman, 2000). While the precise details of the determinants of allergic sensitization and subsequent development of clinical symptoms remain poorly understood, the paradigm in modern allergy teaching is that the tendency to develop atopic disease is a heritable one but that the specific allergic sensitivities exhibited by an individual relate to specific allergen exposures.
Nonallergic rhinitis is characterized by sporadic or persistent perennial nasal symptoms that do not result from IgE-mediated immunopathologic events (Dykewicz, Fineman, Skoner, et al., 1998). The diagnosis of non-allergic rhinitis is frequently a diagnosis of exclusion when an allergic etiology can be substantiated by diagnostic testing. There is no universally accepted classification of non-allergic rhinitis. The symptoms can be similar to allergic rhinitis, but with a decrease in the amount of nasal itch and in the number of sneezing episodes and conjunctival complaints (Jones, 1988; Settipane and Lieberman, 2001). Examples of nonallergic rhinitis include infectious rhinitis, vasomotor rhinitis (noninfectious) and nonallergic rhinitis with eosinophilia syndrome (NARES), overuse of topical-adrenergic agonists/nasal decongestants (rhinitis medicamentosa) and structural or anatomic abnormalities in the nose (including septal deviation or nasal polyposis). Other less common causes of this problem include: endocrine changes of hypothyroid and hyperthyroid disease, pregnancy or damage to sympathetic nerves (Dykewicz, Fineman, Skoner, et al., 1998). Nonallergic rhinitis with eosinophilia is characterized by the presence of nasal eosinophilia without evidence of allergic sensitization. Typical symptoms include perennial symptoms of sneezing, nasal itching, rhinorhoea, nasal obstruction and occasionally loss of sense of smell. It has been associated with non-specifc bronchial hyper-reactivity (Teodoro, Pelucchi, Mastropasqua et al.). It has been suggested that NARES may be linked to aspirin sensitivity (Moneret-Vautrin, Hsieh, Wayoff et al.). The distinction between allergic and nonallergic rhinitis can be difficult clinically. The presence of concurrent symptoms in the eyes or upper respiratory tract such as ocular itching, scratchiness, tearing or redness, palatal itching, or asthma symptoms such as coughing, chest tightness, wheezing and shortness of breath are more likely to suggest allergic rhinitis. The presence of comorbid conditions, such as allergic eczema or asthma, also point toward a diagnosis of allergic rhinitis. Recognition by the patient of trigger factors for symptoms, such as exposure to dusty environments, exposure to cats, dogs or other domestic animals, association of the symptoms with specific seasons, especially spring (tree and grass pollens) or fall (ragweed pollens), all point towards an allergic etiology. In contrast, the symptoms of vasomotor rhinitis are often exacerbated by exposure to nonspecific irritants (non-allergens) such as strong odors, fragrances, perfumes or other volatile chemicals such as exhaust fumes, cigarette smoke or solvents, or by exposure to changes in air temperature or humidity. Additionally, symptoms such as fever, sore throat, generalized malaise or achiness, might point to infectious causes of the rhinitic symptoms (Jones, 1988; Settipane and Lieberman, 2001). While no formal diagnostic criteria have been formulated for distinguishing allergic from vasomotor rhinitis, detailed history taking plays a crucial role in diagnosis.
The exact prevalence of nonallergic rhinitis is not known but estimates indicate that up to 50 percent of patients with rhinitis actually have nonallergic causes (Jones, 1988). Vasomotor rhinitis is more likely to affect adults, and it is more prevalent in women (Settipane and Lieberman, 2001).
In addition to the physical symptoms of allergic rhinitis, such as sneezing, rhinorrhea, nasal pruritus, sufferers from allergic rhinitis also experience symptoms such as significant fatigue, headache, and cognitive impairment. These symptoms in turn are often associated with psychosocial problems, ranging from public embarrassment and diminished physical and emotional well being due to lack of sleep and diminished participation in recreational activities. All told, this can have negative effects on their physical, psychological, and social aspects of their lives significantly because of continued symptoms of allergic rhinitis (Thompson, Juniper, and Meltzer, 2000). Accordingly, the human cost of rhinitis (allergic and nonallergic) is assessed in terms of symptoms, medication needs, interference with sleep, and activities of daily living, work impairment, absences from work and school, impaired learning efficiency, and interference with social commerce.
In a recent pooled analysis of two parallel health outcomes (Tanner, Reilly, Meltzer, et al., 1999) 70 percent of 1,948 patients with moderate-to-severe allergic rhinitis reported embarrassment and/or frustration with allergy symptoms. More that 90 percent believed that their ability to perform daily activities was impaired by allergies, and also reported that their work or classroom performance was negatively affected.
The comorbidities that complicate undertreated allergic rhinitis, typically including asthma, sinusitis and otitis media, add further to the economic and psychosocial burden of disease (Spector, 1997).
Allergic rhinitis is responsible for at least $1.8 billion annually for the direct cost of physician visits and medication expenses (McMenamin, 1994), or nearly 2.5 percent of the $47 billion annual direct cost for respiratory treatment in the United States (Levit, Lazenby, Cowan, et al., 1991; McMenamin, 1994; Rice, Hodgson, and Kopstein, 1985). Furthermore, nearly $3.8 billion was the estimated value of lost productivity to employers and society resulting from allergic rhinitis (Ross, 1996). In the mid-1990s the resulting total annual cost for allergic rhinitis amounted to $5.6 billion.
Retail sales of over-the-counter allergy relief products exceed $140 billion per year, yet only about 12 percent of those affected seek treatment from a doctor, implying that all the other allergic rhinitis sufferers probably self-treat. Because of the significant cost of treatment, it is important that a good method exists for determining resource allocation.
Allergic rhinitis is defined as the clinical expression of tissue changes in the upper airway and adjacent structures following interactions of IgE and specific allergens, characterized by the symptoms of nasal congestion, rhinorrhea, postnasal drainage, sneezing, nasal itching, and occasionally impaired sense of smell (and taste). Allergic rhinitis can be seasonal, usually indicative of pollen-allergen sensitivity, or it can be year-round, frequently related to sensitivity to perennial, indoor aeroallergens. Nonallergic rhinitis is characterized by chronic nasal symptoms, often identical to those of allergic rhinitis but without allergic causation. Nonallergic rhinitis is distinguished by the lack of identifiable triggers in the patient's history, making detailed history taking essential.
The typical findings on physical examination in the patient with allergic rhinitis include pallor of the nasal mucous membranes, which are often engorged. In addition, they often have a bluish tint and frequently exhibit clear watery secretions. There is often enlargement of the inferior turbinates visible by anterior rhinoscopy. The identification of venous engorgement in the infraorbital tissues (allergic shiners), erythema of the conjunctivae, scleral injection, especially when bilateral, adds further evidence to suggest an allergic etiology for the nasal findings.
Absences of fever, oropharyngeal erythema or exudate, or lymphadenopathy in the cervical or submental areas also imply a diagnosis of allergic rhinitis. A history of allergy or atopy in first-degree relatives is also likely to be helpful in forming an opinion as to whether allergic rhinitis is the etiology of the nasal symptoms.
Documenting the presence of IgE antibodies against known aeroallergens substantiates the diagnosis of allergic rhinitis. This can be accomplished either by allergy skin testing with representative aeroallergens or by radioallergosorbent testing (RAST). Skin testing identifies the presence of allergen specific IgE antibodies on tissue bound mast cells in the skin, whereas RAST measures these same antibodies circulating in peripheral blood. In clinical practice, skin testing is generally preferred over RAST testing. Several methods of skin testing are available. Prick-puncture skin tests are considered the most reliable as they show a high degree of correlation with clinical symptoms and provocative allergen challenges. Scratch tests have been shown to be associated with poor reproducibility and possible systemic reactions. They are infrequently used. Intradermal tests, which employ a weak allergen solution, are more sensitive than prick-puncture tests. They can induce false positive reactions (Reid, Lockey, Turkeltaub, et al., 1993) and overall tend to correlate less well with symptoms (Dreborg, Backman, Basomba, et al., 1989). It has been suggested that the availability of standardized extracts may obviate the necessity for intradermal tests (Demoly and Bousquet, 1998; Nelson, Oppenheimer, Buchmeier, et al., 1996; Wood, Phipatanakul, Hamilton, et al., 1999). RAST testing in general correlates closely with the results of skin testing but has a higher cost than does skin testing. RAST tests can yield quantitative results but the titre of specifc IgE measured is frequently not correlated to clinical symptoms.
Because nasal symptoms that occur in nonallergic rhinitis are often indistinguishable from perennial allergic rhinitis, nonallergic rhinitis is often diagnosed by excluding allergic disease by an absence of positive allergy skin tests or negative results by RAST. The use of nasal cytology to evaluate mucosal cellular patterns has the potential to distinguish inflammatory from non-inflammatory nasal conditions, following the course of disease and response to treatment. There is evidence that nasal biopsy is superior to nasal smear for finding eosinophils (Ingels, Durdurez, Cuvelier, et al., 1997)
Antihistamines are an integral component in the treatment of allergic rhinitis, but they are unlikely to be effective in nonallergic rhinitis. In addition, there is increasing support for the position that the primary therapy in confirmed allergic rhinitis should be anti-inflammatory rather than symptomatic. Treating the allergic inflammation has been shown to significantly decrease all the symptoms of allergic rhinitis, not just those mediated by histamine, and also to significantly diminish the complications such as sinusitis and otitis media that frequently occur in patients with allergic rhinitis (Dykewicz and Fineman, 1998).
In contrast, anti-inflammatory therapies such as intranasally applied corticosteroids are often not helpful in other forms of chronic rhinitis such as vasomotor rhinitis where treatment often ends being merely symptomatic in nature. For example, when the dominant symptom is nasal congestion, oral decongestants are recommended, and when the dominant symptom is rhinorrhea, drying agents such as topical ipratropium bromide are more useful. Thus, from a theoretical standpoint, there would indeed appear to be important, therapeutic benefit in distinguishing allergic from nonallergic rhinitis.
Evaluation of the therapies used in allergic rhinitis and nonallergic rhinitis might reasonably include assessments of symptom relief, use of as-needed medications, numbers of days lost from work and school, and estimates of "quality of life." Recent examples of Health-Related Quality of Life questionnaires (HRQOL) used in studies of rhinitis are the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), the Rhinitis Outcomes Monitoring System (ROMS), and the Work Productivity and Activity Impairment (WPAI) survey (Meltzer, 2001).
Environmental control measures to decrease exposure to inciting factors, e.g. allergens, irritants and irritant medications, are considered fundamental to the management of rhinitis (Dykewicz, Fineman, Skoner, et al., 1998). While the established treatment modalities of allergic rhinitis consist of allergen avoidance, anti-allergic medication and immunotherapy (desensitization) for specific allergens, avoidance of exposure to identified aeroallergens is the primary long-term therapeutic modality (Corren, 2000). There now exists sufficient clinical and experimental evidence that such measures are effective and result not only in the diminution of symptoms, but also significantly lessen medication needs as well as decrease associated morbidity from the complications of allergic rhinitis (Woodcock and Custovic, 2000). Allergen avoidance measures, such as removal of feather pillows and down comforters, and encasing mattresses in dust-proof covers to decrease dust-mite exposures as well as elimination of carpeting in favor of tile or hardwood floors and high-flow air filtration units like a HEPA cleaner are all recommended strategies for those with perennial symptoms due to indoor allergens (Arlian and Platts-Mills, 2001; Corren, 2000; Woodcock and Custovic, 2000). Similarly, decreasing exposure in sensitized individuals to domestic animals, especially cats and dogs, has demonstrated efficacy (Chapman and Wood, 2001).
In contrast, outdoor allergens are somewhat more difficult to avoid completely, and recommended measures are to stay indoors and keep windows closed, particularly during periods of the day when certain airborne allergens are at their highest concentration (Corren, 2000).
Current pharmacological treatments for allergic rhinitis include antihistamines (oral and more recently intranasal antihistamines), decongestants (oral and to a lesser extent intra-nasal), and intra-nasally applied anticholinergic agents, all of which are used for symptom relief in rhinitis. Topical nasal corticosteroids and immunotherapy are also useful in suppressing allergic inflammation (Thompson, Juniper, and Meltzer, 2000).
Antihistamines, the most frequently prescribed medication for allergic rhinitis, are usually administered on an intermittent basis for patients with the mildest symptoms. They reduce symptoms of itching, sneezing, and rhinorrhea. Oral antihistamines, which act by competitively inhibiting the binding of histamine to H1 receptors, have arbitrarily been subdivided into first and second-generation categories. Second generation H1 receptor antagonists, such as loratadine, fexofenadine and cetirizine, are less sedating and more pharmacologically selective than earlier antihistamines. In addition, some H1 receptor antagonists have also been reported to inhibit allergen-induced infiltration of tissue by eosinophils, or to actually inhibit release of the mediators, histamine or prostaglandins. These effects are as yet of undetermined clinical relevance and apparently independent of their effects on histamine receptors (Corren, 2000; Kay, 2001; Meltzer, 1995; Nightingale, 1996).
Decongestants, which are sold in either oral or topical form, are often used in combination with antihistamines (Corren, 2000; Meltzer, 1995) and the ineffectiveness of oral antihistamines in relieving nasal obstruction has prompted the subsequent manufacture of agents combining antihistamines and decongestants. By themselves, decongestants help to reduce nasal congestion by their vasoconstrictor properties. Topically applied vasoconstrictor sympathomimetic agents, such as phenylephrine, or imidazoline derivatives, such as oxymetazoline, are effective in inducing nasal capacitance vessel vascular constriction through activation of alpha-adrenergic receptors. Vasoconstriction (nasal decongestion) occurs within five to 10 minutes and may last for six to eight hours with oxymetazoline. These agents are effective for short term use (for example, to assist in physical examination, or to use before air travel, or during the early stages of nasal infections or perhaps during the initiation of treatment with nasal corticosteroids (Beckman and Grammer, 1999; Dykewicz, Fineman, Skoner, et al., 1998; Howarth, 1989; Lund, 1996; Meltzer, 1995).
Oral decongestants (also vasoconstricting agents) include phenylephrine and pseudoephedrine and phenylpropanolamine (The FDA has urged companies marketing phenylpropanolamine to voluntarily withdraw the drug from the market while it initiated regulatory actions to mandate such withdrawals). They cause vasoconstriction by activation of alpha-adrenergic receptors and by indirectly stimulating release of norepinephrine from its storage sites. Although these agents decrease nasal resistance to a lesser degree than do topical agents, their long-term use is somewhat safer because they lack the "rebound" vasodilatation that has been associated with the topical vasoconstrictors. Nasal decongestion occurs within 30 minutes and persists for six to eight hours with oral pseudoephedrine at a dose of 60 mg. Decongestion may last for eight to 12 hours with extended release preparations (Beckman and Grammer, 1999; Dykewicz, Fineman, Skoner, et al., 1998; Howarth, 1989; Lund, 1996; Meltzer, 1995).
Increased cholinergic activity from parasympathetic stimulation is documented in allergic and nonallergic (including infectious) rhinitis (Druce, Wright, Kossoff, et al., 1985; Raphael, Baraniuk, and Kaliner, 1991; White, 1995) resulting in increased nasal secretions and congestion. Anticholinergic medications can cause a reduction in the volume of nasal secretions and some degree of vasoconstriction. Ipratroprium bromide, available as a nasal spray, is a quaternary derivative of isopropyl noratropine and is poorly absorbed by the nasal mucosa and does not cross the blood brain barrier. It has been demonstrated to be effective in reducing rhinorrhea in adults and children with both allergic and nonallergic rhinitis (Bronsky, Druce, Findlay, et al., 1995; Druce, Spector, Fireman, et al., 1992; Georgitis, Banov, Boggs, et al., 1994; Grossman, Banov, Boggs, et al., 1995; Meltzer, 1995; Meltzer, Orgel, Bronsky, et al., 1992).
Intranasal corticosteroids, and to a significantly lesser degree, cromolyn sodium, are anti-inflammatory medications that have been proven effective in treating patients with more pronounced or protracted allergic rhinitis (Weiner, Abramson, and Puy, 1998). The corticosteroids inhibit many of the steps in the cascade of allergic inflammation in allergic rhinitis and are documented to provide excellent symptom relief for all the symptoms of allergic rhinitis, including nasal congestion and blockage (Mygind, Nielsen, Hoffmann, et al., 2001). This has resulted in superior efficacy assessments for intranasal corticosteroids when compared to oral antihistamines in the treatment of allergic rhinitis (Weiner, Abramson, and Puy, 1998). Many formulations of intranasal corticosteroids are currently available. Examples include Nasonex (mometasone furoate), Flonase (fluticasone propionate), Rhinocort (budesonide), Beconase and Vancenase (beclomethasone diproprionate), Nasacort (triamcinolone acetonide), Nasarel and Nasalide (fluniolide) (Allen, 2000; Corren, 1999). The onset of action varies but it is believed that all require three to seven days for optimal effect. There are differences in estimated potency and systemic bioavailablity between the different agents, which might alter the long-term safety profile, but clear differences in clinical efficacy have not been established (Allen, 2000; Corren, 1999). Prophylactic use with initiation of use two weeks in advance of seasonal pollen symptoms has been proposed for maximal symptom reduction. The corticosteroids can inhibit inflammatory responses whether the inciting agent is allergic, chemical or infectious, and there is documented clinical efficacy of these agents in both allergic rhinitis and nonallergic rhinitis (Dykewicz, Fineman, Skoner, et al., 1998).
Cromolyn sodium requires frequent dosing (four times a day) for efficacy, and is also best used prophylactically since its postulated mechanism of action is to prevent mast cell degranulation rather to treat the symptoms of an established allergic reaction in the nose. It may require up to two weeks of continuous usage for maximal clinical effect. Its efficacy in treatment of allergic rhinitis is generally considered to be somewhat less than the antihistamines and significantly less than the intranasal corticosteroids (Brogden, Speight, and Avery, 1974; Dykewicz, Fineman, Skoner, et al., 1998; Meltzer, 1995).
Oral corticosteroids are used for treatment of very severe or intractable nasal symptoms or to treat significant nasal polyposis (Dykewicz, Fineman, Skoner, et al., 1998). They are not recommended for the routine treatment of allergic rhinitis or nonallergic rhinitis
Allergen desensitization immunotherapy is utilized for patients with more severe allergic rhinitis requiring significant amounts of medication or for those who exhibit poor tolerance or non-responsiveness to pharmacological treatment (Kay, 2001). Specific immunotherapy consists of administering increasing concentrations of extracts of allergen over a long period. A typical course of therapy consists of three or more years of subcutaneous injections of the highest or maintenance level of extract at intervals of two to six weeks. Initial therapy requires a series of weekly injections at escalating doses over a period of four to six months in order to induce clinical tolerance to the effective (maintenance) dose (Adkinson, Jr., 1999). Immunotherapy for allergic rhinitis has been reported to be effective and has significant advantages over anti-allergic drugs in that: a) it remains effective for several years after treatment is discontinued (Durham, Walker, Varga, et al., 1999; Mosbech and Osterballe, 1988; Naclerio, Proud, Moylan, et al., 1997) and b) has the potential for decreasing the frequency or intensity of complications or comorbities of allergic rhinitis (Kay, 2001). Due to the increasing costs associated with pharmacotherapy of allergic rhinitis, allergen immunotherapy has been proposed as a cost-effective alternate treatment for allergic rhinitis (Dykewicz, Fineman, Skoner, et al., 1998).
Pharmacotherapy for nonallergic rhinitis therapy can be prescribed either on an as needed basis or as a long-term course of treatment. Until the pathophysiology of non-allergic rhinitis is more clearly delineated, it is unlikely that specific treatments will be identified. To date, most available pharmacotherapeutic approaches are predominantly aimed at symptom relief and can be prescribed either on an as-needed basis or as a long-term course of treatment. Oral decongestants and/or anticholinergics are generally more efficacious than oral antihistamines. However, clinical trials have shown that Azelastine nasal spray (a topical antihistamine) is effective for "total symptom complex" with no discrimination to type of nasal symptom in the treatment of vasomotor rhinitis (Banov, Lieberman, and Vasomotor Rhinitis Study Groups, 2001; Settipane and Lieberman, 2001). Intranasal corticosteroids have also been recommended for long term therapy in nonallergic rhinitis (Jones, 1988; Settipane and Lieberman, 2001). Since the mechanism of vasomotor rhinitis is poorly understood specific therapies are not available and treatments aimed at symptom relief in this syndrome are often not very satisfactory.
Pharmacologic therapies for seasonal and perennial allergic rhinitis do not differ substantively. However, antihistamines for symptom relief are probably more useful in treating seasonal allergic rhinitis (Howarth, 1989; Meltzer, 1995; Scadding, Richards, and Price, 2000), while immunotherapy is more effective in treating seasonal, rather than perennial allergic rhinitis (Adkinson, Jr., 1999). Immunotherapy is effective for perennial allergic rhinitis, but to a lesser extent (Bousquet, Lockey, and Malling, 1998; Kay, 2001). It is unclear whether the difference in efficacy observed with immunotherapy relates more to the constant nature of the allergen exposure in perennial versus seasonal allergic rhinitis or to the nature of the allergens. It should be noted that in the climates of certain geographic locales, perennial symptoms could be pollen-related. On the other hand, intranasal corticosteroids show a significant benefit in treatment for both seasonal and perennial allergic rhinitis (Corren, 1999; Corren, 2000; Howarth, 1989; Weiner, Abramson, and Puy, 1998), but trials have been unable to identify a meaningful difference in efficacy between the different intranasal corticosteroids for seasonal versus perennial allergies (Corren, 1999; Corren, 2000; Dykewicz, Fineman, Skoner, et al., 1998; Howarth, 1989; Weiner, Abramson, and Puy, 1998).
Antihistamines, decongestants, and anticholinergics, which are used primarily for symptom relief in allergic and nonallergic rhinitis, are usually taken on an as-needed basis. In contrast, intranasal corticosteroids are recommended for use on a continuous basis (weeks to months at a time). Because of issues of patient non-compliance with these recommendations, studies are currently underway to determine whether that usage of intranasal corticosteroids on an as-needed basis will prove as effective as regular dosing. One recent study suggests that this might indeed be the case (Jen, Baroody, de Tineo, et al., 2000). As our understanding increases concerning differences in systemic bioavailability of the different preparations of intranasal corticosteroids, further efficacy and relative safety profiles will be warranted (Allen, 2000).
The role of leukotriene modifying drugs in the management of rhinitis (possibly including nonallergic rhinitis), initially developed for use in asthma, is under active investigation. Indeed there are plans to formulate a combination product containing both a second-generation antihistamine and a leukotriene modifying agent (Howarth, 2000; Meltzer, 2000; Mygind, Dahl, and Bisgaard, 2000).
Given the benefits of intranasally applied Azelastine in nonallergic rhinitis (Banov, Lieberman, and Vasomotor Rhinitis Study Groups, 2001), further study of this modality of therapy is warranted. It is unclear whether the benefit in nonallergic rhinitis relates to the antihistaminic activity or associated vasoconstrictor properties of the intranasally applied preparation.
Alternative agents may herald a new era of treatments in rhinitis. As the pathophysiology of allergic rhinitis is becoming elucidated (Kay, 2001), newer biological modifiers are being identified as therapeutic agents or as potential targets of therapy (Kay, 2000). Several of these agents including a soluble recombinant humanized IL4 receptor called altrakincept, anti-IL5, and anti-IL-12 have already undergone clinical study in asthma (Borish, Nelson, Corren, et al., 2001; Bryan, O'Connor, Matti, et al., 2000; Leckie, ten Brinke, Khan, et al., 2000) and studies are planned or underway in allergic rhinitis, nonallergic rhinitis and nasal polyposis. Further evaluation of the promising role of anti-IgE monoclonal antibodies (i.e. omalizumab) in treatment of seasonal and perennial allergic rhinitis (Adelroth, Rak, Haahtela, et al., 2000) are already underway. Strategies directed against adhesion molecules have been considered but it might prove difficult to find targets specific for allergic inflammation that are not intimately involved in other aspects of normal immune functioning (Gundel, Wegner, and Letts, 1993; Wegner, Gundel, Reilly, et al., 1990). The recent discovery of soluble chemo-attractant proteins (chemokines) has provided a molecular basis for many of the observations concerning cellular infiltration in inflammatory processes. The development of antagonists to chemokine receptors offers another strategy for prevention and treatment of inflammation in allergic and possibly nonallergic rhinitis (Frew and Plummeridge, 2001).
The main drawback of antihistamines is their sedative effect, which negatively affects quality of life (Nolen, 1997). Older antihistamines readily cross the blood-brain barrier and bind not only to H1 receptors, but in many cases, also to dopaminergic, serotinergic, and cholinergic receptors (Corren, 2000), which helps account for a host of adverse central nervous system effects (e.g. sedation, fatigue, dizziness, impairment of cognition and performance (Kay, 2000) and anticholinergic effects (e.g. dryness of the mouth and eyes, constipation, inhibition of micturition etc). The newer or second-generation antihistamines such as loratadine, cetirizine and fexofenadine are more pharmacologically selective than earlier antihistamines and are significantly less able to cross the blood brain barrier. Administration of recommended doses of some second-generation antihistamines (fexofenadine and loratadine) results in no greater incidence of sedation than seen with placebo. The reduced incidence of these side effects in second generation antihistamines has greatly improved the usefulness of this category of drug (Kay, 2000). Notably, however, in second-generation antihistamines, reports of sedation and performance impairment increase with upward titration of dosage (Bradley and Nicholson, 1987; Falliers, Brandon, Buchman, et al., 1991; Hindmarch and Shamsi, 1999). Furthermore, some older, nonsedating second-generation antihistamines, such as astemizole and terfenadine may have adverse cardiac effects due to pharmacologic effects on repolarization in cardiac tissue (These 2 agents are no longer available in the United States).
Oral decongestants often produce stimulatory side effects in the central nervous system, causing insomnia, tremor, dizziness, loss of appetite or excessive nervousness, and in the cardiovascular system, resulting in tachycardia, palpitations and hypertension (Dykewicz, Fineman, Skoner, et al., 1998; Meltzer, 1995). These agents should be avoided or used with caution in patients with coronary artery disease, hypertension, hyperthyroidism and elderly patients (Corren, 2000).
The foremost problem with using topical decongestants is its rebound effect. If used longer than three to five days, patients might experience rebound congestion with withdrawal of drug. Continual use over months might even cause development of a form of rhinitis, rhinitis medicamentosa, characterized by persistent nasal congestion which will be difficult to treat effectively (Corren, 2000; Meltzer, 1995).
Intranasal corticosteroid sprays or aqueous forms occasionally have local side effects such as nasal irritation and bleeding. However, these events can be kept to a minimum if the patient is carefully instructed as to the use of the drug. Additionally, there is some concern that systemic corticosteroids might have negative side effects on children including growth retardation, hypothalamic-pituitary-adrenal suppression, and behavioral disturbances (Fireman, 2000; Pedersen, 2001). A recent study (Skoner, Rachelefsky, Meltzer et al, 2000) reported 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. Agents with less systemic bio-availability may be devoid of these risks (Allen, 2000).
Immunotherapy can cause potentially fatal anaphylaxis, with risks being higher during initial dose escalation phase. Therefore, immunotherapy should only be prescribed after careful specialist evaluation and should only be administered under specialist guidance. While systemic reactions are uncommon, physicians administering allergen immunotherapy should be well acquainted with the procedure, and have facilities to administer treatment for acute allergic reactions if they occur. The risk of systemic reactions represents a general limitation in the use of immunotherapy. Risk factors for systemic allergic reactions in allergen immunotherapy have been identified and in addition to dosage escalation, include symptomatic rhinitis and asthma (Fireman, 2000; Lockey, 1995).
This evidence report on the management of allergic rhinitis is based on a systematic review of the literature. Meetings and teleconferences of the EPC staff with technical experts were held to identify specific issues central to this report. A comprehensive search of the medical literature was conducted to identify studies addressing several key questions on the management of allergic rhinitis and nonallergic rhinitis. We compiled evidence tables of study features and results, appraised the methodological quality of the studies, and summarized their results. We identified published meta-analyses on specific treatment topics and evaluated and reported the findings of these reports.
The American Academy of Family Physicians originally proposed this topic and served as the primary science partner of 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 EPC staff to refine key questions, identify important issues, and nominate peer reviewers. The science partners were not involved in the synthesis of evidence or in the writing of this report.
The purpose of an evidence report is to summarize information from relevant studies addressing specific key questions. It is beyond the scope of an evidence report to cover all possible related issues for a topic. The aim of this evidence report is to determine how one diagnoses allergic and nonallergic rhinitis and to determine the minimum level of testing that is needed to differentiate allergic from nonallergic rhinitis; whether differentiating allergic from nonallergic rhinitis is important; the effectiveness of treatments in nonallergic and allergic rhinitis; and how treatment of allergic rhinitis impacts the development of asthma. With input from the science partners of this report, the following key questions (and sub-questions) were formulated. Patient population for this evidence report will include male and female children and adults, minorities, low-income, and elderly patients.
Question 1. How does one diagnose allergic and nonallergic rhinitis (especially vasomotor)?
What differentiates allergic from nonallergic rhinitis with respect to symptoms, signs, physical examination and diagnostic testing?
What is the minimum level of testing necessary to differentiate allergic from nonallergic rhinitis?
Question 2. Is differentiating allergic from nonallergic rhinitis important?
Are treatments different?
Are outcomes different?
Question 3. How does one treat nonallergic and allergic rhinitis?
For nonallergic rhinitis:
What is the efficacy of antihistamines (all classes), nasal corticosteroids, sympathomimetics, or leukotriene modifiers compared with placebo?
What are the side effects due to antihistamines, nasal corticosteroids, immunotherapy, sympathomimetics, cromolyn, and leukotriene modifiers?
For allergic rhinitis:
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).
What are the side effects/adverse events due to: antihistamines, nasal corticosteroids, sympathomimetics, leukotriene modifiers?
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?
What is the likelihood of developing asthma with untreated allergic rhinitis (natural history)?
How does treatment of allergic rhinitis affect the likelihood of developing asthma?
How does treatment of allergic rhinitis affect the likelihood of developing bacterial sinusitis?
Studies for the review of the primary literature were identified primarily through a Medline search of English language literature conducted 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.
Medline search results were screened and potential studies were identified for retrieval based on setting, study question, population, and disease. Articles involving minority populations and gender issues were especially searched for (although none were found). Studies with no specific reference to allergic or nonallergic rhinitis were excluded. After retrieval, each paper was screened to verify that the condition and treatments under investigation were appropriate to each study question.
The Medline search yielded 3,381 citations. 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 and these are discussed below.
Question 1: Diagnosis of Allergic and Nonallergic Rhinitis
We included 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.
Question 2: Differentiation of Allergic from Nonallergic Rhinitis
We included cross-sectional and prospective studies addressing diagnostic methods of differentiation of allergic from nonallergic rhinitis.
Question 3: Treatment of Allergic and Nonallergic Rhinitis
We included randomized controlled trials (RCTs) 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 inhibitors, and sympthomimetics. In the treatment of nonallergic rhinitis we included randomized controlled trials of antihistamines, nasal corticosteroids, anticholinergics, and sympathomimetic agents. We excluded uncontrolled trials, case reports, and case series.
Question 4: Impact of Treated and Untreated Allergic Rhinitis on Development of Asthma and Bacterial Sinusitis
We included prospective studies evaluating the relationship between allergic rhinitis and later development of asthma or bacterial sinusitis. Cross-sectional studies, case reports, and case series were excluded.
We placed no restrictions on the patients' gender or ethnicity. Specifically, AAFP was interested in studies about minorities, low-income, and elderly patients. However, we found no study that addressed these populations in its entirety or as subgroups.
After categorizing all retrieved studies according to the above criteria a total of 88 studies qualified for data abstraction. Data for evidence tables were abstracted using the forms shown in the appendix. Information abstracted included the study population characteristics, inclusion and exclusion criteria, the descriptions and the diagnostic criteria, potential verification bias as well as the main results and the conclusions of the study. In addition, data for quality assessment of individual studies were systematically abstracted. Data were abstracted by one member and then verified by a second member. If two abstractors disagreed, a third party methodological expert resolved the dispute.
The evidence we found is summarized in three complementary forms. The evidence tables provide detailed information about key features of study design and results of all the studies reviewed. A narrative and tabular summary of the strength and quality of the evidence of each study are provided for each drug class.
For each of the study questions, separate evidence tables were constructed for the allergic and nonallergic populations. These tables are presented under the Evidence Tables section of this evidence report. The evidence tables list the clinical studies found for each of the drug class comparisons and that met the inclusion criteria. The specific information included in the evidence tables is described above.
Grading of the evidence can be useful by indicating the overall "quality." A simple evidence grading system using a single scale may be desirable, however, the "quality" of evidence is multi-dimensional, and a single metric cannot fully capture information needed to interpret a clinical study (Lowell and Franklin, 1965; Settipane, 1986; Silberg, Lundberg, and Musacchio, 1997; Varley, 1964). We believe that information on individual components of a study contribute more to the evaluation of evidence by deliberating bodies than a single summary score. The evidence-grading scheme we used here assesses four dimensions that are important for the proper interpretation of the evidence:
study size
applicability
summary of efficacy and safety outcomes
methodological quality
The study (sample) size is used as a measure of the weight of the evidence. A large study provides a more precise estimation of the treatment effect but does not automatically confer broad applicability unless the study included a broad spectrum of patients. Very small studies, taken individually, cannot achieve broad applicability. But several small studies that enrolled diverse populations, taken together, may have broad applicability. The study size is included as a separate dimension used to assist the assessment of applicability. For summarizing all studies, this would be the number of studies and the total number of patients in these studies.
Applicability, also known as generalizability or external validity, addresses the issue of whether the study population is sufficiently broad to be generalizable to the population at large. Individual studies are often unable to achieve broad applicability due to restricted study population characteristics and a small number of study subjects (Lau, Ioannidis, and Schmid, 1997). We define the applicability grade as below:
Patients enrolled in the trial represent a broad spectrum of the population (high degree of applicability). Typically this would be a large study, although a large study in itself does not guarantee a high degree of generalizability.
The study included only a narrow/restricted study population, but the result is relevant to similar types of patient population (restricted applicability). Typically this would be a small study, but may also be a large study of a very homogeneous population.
Narrow sample, not well generalizable to other groups, or studied outlier population that is not immediately relevant to the study question (very limited direct applicability or not applicable), or where the study reported only limited information.
N.D. No data or insufficient information reported to assess the applicability.
Methodological quality or internal validity addresses the design, conduct, and reporting of the clinical trial. Some of the items belonging to this entity are widely used in various "quality" scales and usually include items such as concealment of random allocation, treatment blinding, and handling of dropouts. Most of the studies included in this evidence report are randomized controlled trials, we define a three categories scale to report the methodological quality: A (least bias), B (susceptible to some bias), or C (likely to have large bias).
Double-blinded, well-concealed randomization, few drop outs, and no (or only minor) reporting problem of the trial that is likely to cause significant bias.
Single-blinded only, unclear concealment of randomization, or has some inconsistency in the reporting of the trial but is unlikely to result in major bias.
Unblinded study, inadequate concealment of random allocation, high drop-out rate, or has substantial inconsistencies in the reporting of the trial such that it may result in large bias.
Outcomes studied included the effect of nasal corticosteroids vs. antihistamines, sedating vs. nonsedating antihistamines, cromolyn sodium, anticholinergic agents, leukotriene inhibitors, and sympathomimetics in both allergic and nonallergic rhinitis. In addition, we examined the evidence for a causal link between allergic rhinitis and development of asthma or bacterial sinusitis.
The efficacy outcomes reported by most studies addressing the same question in this evidence report were often heterogeneous and not readily amenable to meta-analysis. Different studies often used different combinations of outcomes such as watery eyes, itchy eyes, rhinorrhea, sneezing, itchy nose, and nasal congestion. Outcomes were typically assessed using categorical scales but the range of scales varied across studies.
Summarizing side effects is also problematic due to non-standard reporting of these outcomes by individual studies. Studies frequently do not define side effects, do not report the same side effects or do not use the same metric to report the same side effect, and many studies do not report side effects.
The evidence tables report detailed information about the outcomes. The summary tables in the result section report primarily the nasal symptoms. Consistency of effect across most studies addressing the same question is used as an indication of efficacy for the treatment being evaluated.
The MEDLINE® search identified 3,354 citations. We retrieved 228 articles for evaluation and included 88 into the evidence report. Among these 88 studies, 86 were RCTs and two were prospective cohort studies. Of the 86 randomized trials, 77 were double-blinded, six were single-blinded and in three studies the type of blinding was unstated. Forty-four of the 86 randomized trials reported the source of funding. Ninety-one percent of these 44 trials reported funding by pharmaceutical companies. There were only four trials supported by government funding.
There were no specific studies of the pediatric population. Even though some studies may have enrolled patients in pediatric ranges, separate data was not reported for this subgroup. Therefore, no specific conclusions could be drawn for the pediatric population.
No studies addressing these questions met the criteria described in the methods section of this report. Specifically, no studies were identified which sought to differentiate between allergic and nonallergic rhinitis on the basis of clinical symptoms or signs on physical examination. We found no study that evaluated a test specifically to diagnose nonallergic rhinitis.
One study was identified which sought to develop criteria for the definition of allergic rhinitis through a systematic evaluation of the relative importance of symptoms, signs and investigative tests (Ng, Warlow, Chrishanthan, et al., 2000). This study compared patients with diagnosed allergic rhinitis to normal individuals. It did not attempt to differentiate symptoms and signs between allergic and nonallergic rhinitis. It was suggested in that study that in establishing a diagnosis of allergic rhinitis the relative importance of skin prick testing is equal to a history of allergen-induced nasal and ocular symptoms. However, most authorities recommend confirmatory testing (Dykewicz, Fineman, Skoner, et al., 1998). Discordance between history and skin tests (or other diagnostic tests) is observed.
Due to the lack of studies that directly address this question, we therefore undertook an analysis of the inclusion criteria employed in those randomized controlled clinical trials addressing treatment issues in vasomotor rhinitis. In the majority of cases (7 out of 10 evaluable studies: Broms and Malm, 1982; Graf, Enerdal, and Hallen, 1999; Jokinen and Sipila, 1983; Kirkegaard, Mygind, Molgaard, et al., 1987; Kirkegaard, Mygind, Molgaard, et al., 1988; Nelson and Jacobs, 1982; Sjogren, Jonsson, Koling, et al., 1988) exclusion of allergic disease by an absence of positive allergy skin tests or negative results by RAST is the usual prerequisite criterion for diagnosing vasomotor rhinitis. The term vasomotor rhinitis will be used preferentially, since in all the studies we analyzed every otherwise identifiable form of rhinitis was excluded.
Vasomotor rhinitis can occur as an isolated condition, characterized by an increase in nasal symptoms attributable to exposures to nonspecific irritants such as strong odors, fragrances or perfumes, or indeed to changes in air pressure and temperature. Importantly, however, it can also occur in conjunction with (possibly as a complication of) allergic rhinitis.
Given the absence of well-designed studies addressing these questions, we can only report that, based on current clinical practices and the analysis of the inclusion criteria employed in studies of vasomotor rhinitis, diagnostic testing rather than signs and symptoms is necessary to differentiate isolated vasomotor rhinitis from allergic rhinitis.
The minimum level of testing necessary to confirm or exclude a diagnosis of allergic rhinitis has not been established. The small study by Ng, Warlow, Chrishanthan, et al. (2000) suggests that total serum IgE may be as useful as specific allergy skin prick tests which in turn are more useful than RAST-type testing in confirming a diagnosis of allergic rhinitis.
Henderson, Swedlund, and Van Delen (1971) conducted a prospective study in an adult allergy clinic and observed elevated serum IgE in 10% of patients with non-allergic rhinitis and in 62% of allergic rhinitis patients. A larger study by Wittig, Belloit and De Fillippi (1980) employed different cutoff levels of serum IgE to look at diagnostic sensitivity and specificity in rhinitic individuals and reported 98% specificty with the highest cutoff level but with a sensitivity of only 30%. Reduction of the cutoff level allowed an increase in sensitivity to 60% but a drop in the sensitivity to 80%. These studies suggest limited value for serum IgE in screening for allergic rhinitis.
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. As seen in the evidence tables, similar treatments are frequently employed in the two conditions. However, what has been studied in the literature does not imply that differentiation might be important. It is generally believed that environmental control and immunotherapy have relevance only for treatment of allergic rhinitis. Therefore, differentiation is important for these two interventions.
Similar treatment modalities have been employed in RCTs in both conditions and include antihistamines, decongestants, nasal corticosteroids, cromoglycate, ipratropium bromide and other agents.
The evidence tables and the details elaborated below indicate the difference in success rates of the various treatment modalities.
Studies looking at the various treatments employed in the treatment of nonallergic rhinitis are summarized in the evidence tables. Only one study (Broms and Malm, 1982) meeting the criteria for inclusion looked at the role of antihistamines in the treatment of nonallergic rhinitis. In this study, the antihistamine was used as part of antihistamines-decongestants combination product and accordingly, outcomes related to the antihistamine component of this drug cannot be separately identified. The FDA has approved a nasal topical product - azelastine (an H1 antihistamine) for treatment of vasomotor rhinitis.
A small number of studies have looked at the benefit of nasal corticosteroids in this condition. In a double-blind placebo controlled trial, Wight, Jones, Beckingham, et al. (1992) showed a significant improvement in the symptom of nasal obstruction with each of two doses of budesonide. No other symptoms were altered, no difference was seen between the two doses and no significant side-effects were recorded. Comparisons of nasal corticosteroids and ipratropium in nonallergic rhinitis (NAR) yield conflicting results. Bende and Rundcrantz (1985) compared budesonide with ipratropium and showed a superior effect for budesonide with respect to symptoms of nasal secretion and sneezing. Jessen and Bylander (1990) report a double blind RCT comparing ipratropium and beclomethasone in 24 patients with NAR characterized by hypersecretion. No difference was identifiable between the efficacy of the two medications.
Two randomized controlled studies were identified which looked at the role of oral decongestants (phenylpropanolamine) in treatment of nonallergic rhinitis. In both studies emphasis was placed on relief of symptoms of nasal congestion. One study additionally focused on nasal sneezing while the other study focused additionally on rhinorrhea. The first study (Broms and Malm, 1982) contained data which were difficult to abstract, but did suggest a decrease in symptoms of nasal congestion by phenylpropanolamine. The second study (Renvall and Lindqvist, 1979) indicated that phenylpropanolamine was not superior to placebo in terms of relief of nasal congestion at a dosage of 50 mg per day with approximately 50 percent of patients reporting no improvement or worsening at this dosage. At a dosage of 100 mg per day there was a statistically significant improvement in symptoms of nasal obstruction with respect to placebo and also with respect to phenylpropanolamine 50 mg. The lower dosage was also poorly effective in alleviating symptoms of increased nasal secretion, whereas the 100 mg per day dosage was significantly more effective in relieving this symptom than the lower dose. The FDA has urged companies marketing that decongestant, phenylpropolamine, to voluntarily withdraw the drug from the marketplace, while it initiated regulatory actions to mandate such withdrawals.
No studies were identified looking at the efficacy of leukotreine modifiers in the treatment of nonallergic rhinitis.
Five randomized controlled clinical trials were identified addressing the efficacy of anticholinergic agents in the treatment of nonallergic rhinitis. All of the studies are rated B for methodological quality and the median grade for applicability is rated II. Each of these five trials studied intranasal ipratropium bromide, and each of the five studies documented efficacy for ipratropium in reducing nose blowing frequency and rhinorrhea. The first study (Kirkegaard, Mygind, Molgaard, et al., 1988) (n=38) documented a significant reduction in mean daily episodes of nose blowing by treatment with 80 micrograms q.i.d. of ipratropium. The second study (Sjogren, Jonsson, Koling, et al., 1988) (n=24) documented a dose-dependent decrease in methacholine induced nasal secretions by treatment for one day with doses of ipratropium of 40 micrograms, 100 micrograms and 200 micrograms. The third (Jokinen and Sipila, 1983) documented a physician rated significant reduction in the symptoms on rhinorrhea with ipratropium but no effect on the symptoms of nasal congestion, sneezing or nasal itching. The fourth study (Kirkegaard, Mygind, Molgaard, et al., 1987) compared two doses of ipratropium (80 micrograms q.i.d. versus 400 micrograms q.i.d.) to placebo. Both doses resulted in a significantly decreased mean daily number of nose blowing episodes compared to placebo, but 400 micrograms q.i.d. being significantly more effective than 80 micrograms q.i.d. No effect was observed on symptoms of nasal congestion or sneezing. The final study (Malmberg, Grahne, Holopainen, et al., 1983) also documented a significant reduction in the number of nose blowing episodes as well as a significant reduction in the symptom of rhinorrhea with ipratropium compared to placebo. No effect was seen on nasal congestion.
Two RCTs were identified looking at the effects of cromoglycate in nonallergic rhinitis. Both studies recorded improvement in symptoms of rhinitis with active treatment compared to placebo. In the first study (Balle and Illum, 1977) cromoglycate resulted in a significant decrease in sneezing and congestion scores. In the second (Nelson and Jacobs, 1982) cromoglycate was documented to produce a significant decrease in nasal itching but no change in the other three symptoms evaluated.
Adverse events of antihistamines described included drowsiness, nausea, and headache. This study (Broms and Malm, 1982) involving a combination product (antihistamine plus decongestants) also had patients who described micturition difficulties. This is presumed to be related to the anticholinergic activity of the antihistamine component.
In three of the five studies looking at ipratropium in treatment of nonallergic rhinitis, significant side-effects of nasal dryness and nasal irritation were recorded (Jokinen and Sipila, 1983; Kirkegaard, Mygind, Molgaard, et al., 1988; Malmberg, Grahne, Holopainen, et al., 1983).
In the two studies looking at cromoglycate in nonallergic rhinitis no significant adverse effects were associated with use of this medication (Balle and Illum, 1977; Nelson and Jacobs, 1982).
[See Evidence Tables 2-5]
A recent meta-analysis of 17 RCTs published up to 1997 compared intranasal corticosteroids with antihistamines in the treatment of seasonal and/or perennial allergic rhinitis (Weiner, Abramson, and Puy, 1998). The analysis included several different nasal corticosteroid preparations and several different antihistamines including both nonsedating and sedating antihistamines. The analysis reported that for the six nasal symptoms studied as well as for overall nasal symptoms score nasal corticosteroids produced significantly greater relief than did oral antihistamines. The specific symptoms that were improved included nasal blockage, nasal discharge, sneezing, or nasal itching and postnasal drainage. There were no significant differences identified between treatments for nasal discomfort, nasal resistance or eye symptoms. Three of the 17 RCTs address the issue cost effectiveness of intranasal corticosteroids versus oral nonsedating antihistamines with results favoring use of nasal corticosteroids in each case.
Our search identified eight additional studies that were not included in the meta-analysis undertaken by (Weiner, Abramson, and Puy, 1998). Seven of the studies favored intranasal corticosteroids over antihistamines both with respect to improvement in global nasal symptoms as well as most individual nasal symptoms. One study (D'Ambrosio, Gangemi, Merendino, et al., 1998) showed better symptom improvement with cetirizine alone over fluticasone alone. Thus, the overwhelming majority of studies show very clear benefits for the use of intranasal corticosteroids over either sedating or nonsedating antihistamines for relief of symptoms of nasal allergy. These results are similar for seasonal allergic rhinitis and perennial allergic rhinitis.
No RCTs were identified directly comparing immunotherapy with antihistamines in the treatment of seasonal and/or perennial allergic rhinitis. Immunotherapy is generally considered a long-term disease modifying treatment measure requiring months to years of treatment whereas antihistamines are often used for immediate symptom relief. Therefore direct comparisons with respect to efficacy are not likely to be undertaken.
No RCTs were identified directly comparing immunotherapy with intranasal corticosteroids in the treatment of seasonal and/or perennial allergic rhinitis.
The efficacy of subcutaneous specific allergen immunotherapy has been documented in more than 40 placebo-controlled trials in allergic rhinitis. These studies frequently employ immunotherapy as an add-on treatment and do not compare it to other active treatment. Efficacy has been demonstrated in allergic rhinitis for many different inhalant allergens including tree pollens, grass pollens, ragweed pollens, other pollens, dust mite, cat and the mold alternaria (Bousquet, Lockey, and Malling, 1998; Bousquet 2001).
Eight randomized controlled clinical trials were identified in which a direct comparison between nonsedating and sedating antihistamines in the treatment of seasonal allergic rhinitis were undertaken. Three of these studies (including approximately 589 patients) implicated superior relief of nasal symptoms by the sedating antihistamines (Gutkowski, Del Carpio, Gelinas, et al., 1985; Johansen, Bjerrum, and Illum, 1987; Thoden, Druce, Furey, et al., 1998). One other study (including approximately 138 patients) indicated superior relief of nasal symptoms by the nonsedating antihistamine (Backhouse and Rosenberg, 1987). The remaining four studies (including approximately 507 patients) showed no difference with respect to nasal symptoms between the two treatment arms (Buckley, Buchman, Falliers, et al., 1988; Hugonot, Hugonot, and Beaumont, 1986; Malmberg, Grahne, Holopainen, et al., 1983; Pastorello, Ortolani, Gerosa, et al., 1987). These results are interpreted as indicating no consistent benefit of sedating antihistamines over nonsedating antihistamines with respect to symptom alleviation in allergic (seasonal) rhinitis. In most of these studies an array of symptoms was evaluated (including nasal itching, sneezing, rhinorrhea, nasal congestion, post nasal drainage), and in most cases changes in symptoms tended to correlate with one another with respect to favoring either sedating or nonsedating antihistamines. Accordingly, emphasis is placed upon the global evaluation of symptom change for the purpose of this reporting. Changes in ocular symptoms were not included in this data analysis.
Two additional studies did not give outcomes in terms of improvement of nasal symptoms. Gastpar and Dieterich (1982) studied changes in IgE values, and Weiler, Bloomfield, Woodworth, et al. (2000) studied side-effects.
An additional two RCTs were identified in which a direct comparison between nonsedating and sedating antihistamines in the treatment of perennial allergic rhinitis were undertaken. One of these studies (Brostoff and Lockhart, 1982) showed no statistical difference between the groups with respect to treatment of nasal symptoms with both treatments being assessed as extremely effective. The other study (Druce, Thoden, Mure, et al., 1998) showed significant benefits in favor of the sedating antihistamine brompheniramine over loratadine with respect to each nasal symptoms evaluated. These results are interpreted as indicating no consistent benefit of nonsedating antihistamines over nonsedating in perennial allergic rhinitis.
In all studies except for two, significant improvements in symptoms of allergic rhinitis were reported in those patients treated with cromoglycate compared to those patients treated with placebo.
In 16 of the studies, three or more of the five common symptoms associated with allergic rhinitis (nasal itch, sneezing, rhinorrhea, nasal congestion, or postnasal drainage) were significantly improved by treatment with cromoglycate compared to placebo. No consistent pattern of nonresponsiveness to cromoglycate with respect to a given symptom was identifiable across the studies. In five of the 13 studies that indicated failure of some symptoms to respond to treatment with cromoglycate, congestion was identified as one of the nonresponsive symptoms.
Eighteen studies (14/18 studies of seasonal allergic rhinitis and 4/11 studies of perennial allergic rhinitis) included documentation of patient preference or patient willingness to use the drug in the future. In 17 studies there was a clear-cut preference for the active ingredient (cromoglycate). One study of cromoglycate in perennial allergic rhinitis fails to document a significant improvement in symptoms or a patient preference for future usage.
Overall, cromoglycate is an effective treatment for reducing symptoms associated with allergic rhinitis (30 of 32 studies). It seems to have higher efficacy in seasonal allergic rhinitis than it does in perennial allergic rhinitis. In those studies that looked at different dosing regimens, higher doses (including higher frequency of dosing) were more effective.
A single study was identified in seasonal allergic rhinitis looking at the efficacy of nedocromil compared with placebo in reducing symptoms of allergic rhinitis. It showed a significant reduction in daily nasal itch and rescue antihistamine usage. It showed no benefits for symptoms of sneezing, rhinorrhea, and nasal congestion even though 63 percent preferred this medication and 30 percent preferred placebo.
Oral alpha-adrenergic agents, such as pseudoephedrine, phenylephrine and phenylpropanolamine cause nasal vasoconstriction. Two clinical trials were identified looking at the effects of decongestant drugs in allergic rhinitis and suggest some benefit in relief of nasal congestion but not other symptoms.
[See Evidence Tables 2-3]
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 steriods, in the short-term treatment studies analyzed. However, a recent study (Skoner, Rachelefsky, Meltzer et al, 2000) reported 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. Agents with less systemic bio-availability may be devoid of these risks (Allen, 2000).
No major adverse events were reported in studies of cromolyn. Minor reported side-effects included a high frequency of nasal irritation (18/29 studies), headache, and nasal congestion.
We found no data to address this question. None of the studies categorized patients by disease severity or concurrent disease when addressing either efficacy or safety.
Identify and review relevant published meta-analyses in the following treatment areas:
No meta-analyses were identified.
Ross, Nelson, and Finegold (2000) report a meta-ananlysis of the efficacy of specific immunotherapy in the treatment of allergic rhinitis. Inclusion criteria required of the published studies were prospective nature, double blinding, placebo control and citation in MEDLINE® between 1966 and 1996. Data from sixteen studies (including 759 patients) were combined. Fifteen of 16 studies concluded that specific immunotherapy was effective and the analysis showed a significant effect in improvement in both symptom control and symptom medication scores in allergic rhinitis.
No meta-analysis addressed the specific comparison posed in this question. However a meta-analysis looking at studies which compared nasal corticosteroids to oral antihistamines by Weiner, Abramson, and Puy (1998) is identified and has been discussed above.
No meta-analyses were identified addressing this question.
It has long been recognized that there is an association between allergic rhinitis and asthma. A large number of cross-sectional studies have shown the prevalence of allergic rhinitis in asthmatic patients to be between 28 and 78 percent, compared with approximately 20 percent in the general population. In addition, prevalence of asthmatic symptoms amongst allergic rhinitis patients is reportedly between 19 and 39 percent of patients, again significantly higher than the 5 percent rate in the general population (Blair, 1977; Pedersen and Weeke, 1983; Settipane, 1986; Smith, 1983). Other cross-sectional studies have attempted to elucidate the temporal relationship between allergic rhinitis and asthma. In one study of 7662 subjects, 49 percent of patients with both asthma and allergic rhinitis reported onset of rhinitis symptoms prior to asthma symptoms, and 25 percent of patients experienced the onset of asthma within one year of developing allergic rhinitis (Pedersen and Weeke, 1983). Other studies demonstrated a similar temporal relationship. In addition, it is known that patients with allergic rhinitis commonly exhibit bronchial hyperreactivity. However, in order to illustrate a causal relationship between allergic rhinitis and asthma, well-conducted prospective cohort studies are necessary. We identified two such studies in our literature search. The first study (Settipane, Hagy, and Settipane, 1994) followed a group of college students for 23 years and found that those students with allergic rhinitis at the beginning of the study were three times more likely to develop asthma during followup than non-atopic controls. A similar study by Anderson, Pottier, and Strachan (1992) followed 7,225 children from birth to age 23 and found that children with allergic rhinitis were 2.7 to 3.0 times more likely to develop asthma during followup.
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 link between these two diseases and an ability to impact certain characteristics of asthma by use of nasal corticosteroids in treatment of allergic rhinitis. Conventional doses of cetirizine, loratadine and oral decongestants have been reported to improve asthma symptoms and pulmonary function in patients with allergic rhinitis (Corren, Harris, Aaronson, et al., 1997; Grant, Nicodemus, Findlay, et al., 1995).
It is known that there is a link between allergic rhinitis and rhinosinusitis. Cross-sectional studies have shown an increased prevalence of acute and chronic bacterial sinusitis amongst allergic rhinitis patients. Similarly there is an increased prevalence of atopy and allergic rhinitis amongst 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 required. We identified no studies meeting these criteria in our literature search.
This report summarizes the scientific evidence on four specific questions and associated subquestions in the diagnosis and treatment of allergic and nonallergic rhinitis. The results presented in Chapter 3 are based on the screening of 3,354 MEDLINE titles and 228 full articles, 86 of which were the RCTs and the two prospective cohort studies analyzed in this report. The analysis also describes the limitations of the existing evidence base related to the questions of interest.
In addition to the conclusions described in this chapter, we believe that the data support the following observations:
Most of the clinical trials were supported by pharmaceutical companies.
There are 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.
The number and size of trials in nonallergic rhinitis were small overall. There were 13 trials, from the period 1982 through 1999, which enrolled some 450 patients. In several comparisons of interest, trials were very small - 20 to 30 patients. There were no studies examining the efficacy of leukotriene modifiers. There were only two randomized controlled studies, with 90 enrolled patients, which examined the role of and oral decongestants for the relief of symptoms of nasal congestion. The FDA has urged companies marketing that decongestant, phenylpropolamine, to voluntarily withdraw the drug from the marketplace, while it initiated regulatory actions to mandate such withdrawals.
Almost all the studies analyzed were RCTs, though most of the evidence for efficacy is based on studies that were given a 'B' or 'C' methodological quality rating, indicating the failure to 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 was not reported for this subgroup. Therefore, no specific conclusions could be drawn for the pediatric population.
In this analysis, there were no studies identified hat specifically sought to differentiate between allergic and nonallergic rhinitis on the basis of clinical symptoms, or signs on physical examination, or the presence or absence of comorbid conditions. More importantly, no studies addressing the question of what minimum level of diagnostic testing is necessary to differentiate between allergic and nonallergic rhinitis 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 addressing this question, we can only report that, based on current clinical practices and the analysis of the inclusion criteria employed in studies of nonallergic rhinitis, diagnostic testing rather than symptoms or signs is generally recommended to differentiate isolated vasomotor rhinitis from allergic rhinitis. Diagnostic tests employed fall into two categories: allergy skin testing and RAST.
The minimum level of testing necessary to confirm or exclude a diagnosis of allergic rhinitis has not been established in the literature. The study by Ng, Warlow, Chrishanthan, et al. (2000) suggests that total serum IgE may be as useful as specific allergy skin prick tests, which, in turn, are more useful than RAST-type testing in confirming a diagnosis of allergic rhinitis.
While the importance of distinguishing between allergic and nonallergic rhinitis has not been addressed directly and specifically by the published literature, the results suggest that this distinction is important. Different modalities of pharmacologic therapy for each diagnosis are supported by the literature and, perhaps more importantly, complications or comorbid conditions such as asthma and sinusitis can be impacted by the choice of pharmacotherapy for the underlying rhinitis. One of the potential benefits of differentiating allergic from nonallergic rhinitis would be that only allergic rhinitis can benefit from environmental control measures and immunotherapy.
Certain treatment modalities are well-established in the management of allergic rhinitis (for example, intranasal corticosteroids and oral antihistamines). A small number of studies (3, with a total of 97 patients) have looked at the benefit of nasal steroids in the treatment of nonallergic rhinitis, one with conficting results. However, intranasal corticosteroids are recommended for long-term therapy in nonallergic rhinitis. The FDA has approved two nasal corticosteroids for treatment of nonallergic rhinitis and has also approved one nasal topical product - azelastine (an H1 anithistamine) for treatment of vasomotor rhinitis.
There is some evidence for linkage between allergic rhinitis and asthma and there is also a small body of evidence indicating that appropriate treatment of allergic rhinitis by intranasal corticosteroids may have salutary effects on the features of asthma. Sinusitis is also a well-described secondary complication of allergic rhinitis. Therefore, it is possible that inappropriate diagnosis and treatment of allergic rhinitis may increase the pharmacoeconomic and socioeconomic burden of sinusitis.
Only one published study meeting the criteria for inclusion examined the role of antihistamines in the treatment of nonallergic rhinitis. Because the antihistamine was used as part of an antihistamine-decongestant combination product, outcomes related to the antihistamine component of this drug cannot be separately identified. Two additional studies published after the completion of the literature search (Banov and Lieberman, 2001, Gehanno, Deschamps, Garay et al., 2001) demonstrated the efficacy of azelastine nasal spray for the treatment of vasomotor rhintis.
Though it is commonly assumed that many physicians recommend a therapeutic trial with nasal corticosteroids in the management of nonallergic rhinitis, there were only three studies identified which examined the efficacy of nasal corticosteroids in the treatment of nonallergic rhinitis. Two of the three studies employed budesonide and the other used beclomethasone. One study indicated that the symptoms of nasal congestion could be 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 and the other study failed to differentiate between the two on the basis of symptom relief. Intranasal corticosteroids have been recommended for long term therapy for nonallergic rhinitis (Settipane and Lieberman, 2001) and two nasal corticosteriods have FDA approval.
Only two randomized controlled studies were identified which looked at the role of oral decongestants (phenylpropanolamine) in treatment of nonallergic rhinitis. In both studies emphasis was placed on relief of symptoms of nasal congestion. Phenylpropanolamine was demonstrated in both trials to be helpful in the management of nasal congestion when used at sufficient dosages (e.g. 100 mg per day dosage). No major impact on the other associated symptoms experienced by patients with nonallergic rhinitis was observed in these studies.
While small in number, these studies do suggest a role for decongestants in treatment of nonallergic rhinitis with specific emphasis on the 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 of the clinical trials concerning management of nonallergic rhinitis.
No studies were identified looking at the efficacy of leukotriene modifiers in the treatment of nonallergic rhinitis.
Each of five studies identified in the analysis indicated a significant benefit from use of nasal ipratropium bromide (a topically applied anticholinergic agent) in the treatment of the symptom of rhinorrhea (increased nasal secretions) associated with nonallergic or vasomotor rhinitis. Relief of the symptom is dose-dependent - dosing often up to four times a day was required to achieve a significant clinical benefit. Other symptoms such as nasal congestion, nasal itching and sneezing do not appear to be benefited by ipratropium bromide.
Both of the two RCTs that examined the effects of cromoglycate in nonallergic rhinitis recorded improvement in symptoms of rhinitis with active treatment compared to placebo. Not all symptoms were improved by cromoglycate in either study and the specific symptoms which benefited most differed between these two studies. However, although small in quantity, the data appear to indicate that sodium cromoglycate may have a role in the management of nonallergic rhinitis.
There were no side-effects or adverse events reported in the studies of antihistamines or nasal corticosteroids. However, a recent study (Skoner, Rachelefsky, Meltzer et al, 2000) reported 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. Agents with less systemic bio-availability may be devoid of these risks (Allen, 2000).
In the two studies examining cromoglycate, no significant adverse events were associated with use. In only one of the two studies involving sympathomimetics were adverse events such as drowsiness, nausea and headache described. This study (Broms and Malm, 1982), involving a combination product (antihistamine plus decongestants) also had patients who described micturition difficulties, which were presumed to be related to the anticholinergic activity of the antihistamine component. Significant side-effects of nasal dryness and nasal irritation were recorded in three of the five studies looking at ipratropium in the treatment of nonallergic rhinitis. Overall, these treatment modalities are very well tolerated and devoid of major side-effects.
In conclusion, the literature 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. All treatments appear relatively free of major side-effects. Oral decongestants are effective in controlling the symptom of nasal congestion and ipratropium bromide is beneficial in the management of rhinorrhea. With the exception of azelastine for treatment of vasomotor rhinitis, there is little published evidence for use of antihistamines or nasal corticosteroids for the management of nonallergic rhinitis.
There is strong evidence for the beneficial effects of nasal corticosteroids in the management of allergic rhinitis, and these agents are significantly superior to antihistamines.
The recent meta-analysis by Weiner (Weiner, Abramson, and Puy, 1998) of 17 RCTs published up to 1997 compared intranasal corticosteroids with antihistamines in the treatment of seasonal and/or perennial allergic rhinitis. The analysis included several different nasal corticosteroid preparations and several different antihistamines including both nonsedating and sedating antihistamines. For the six nasal symptoms studied as well as for overall nasal symptoms score, nasal corticosteroids produced significantly greater relief than did oral antihistamines. The specific symptoms that were improved included nasal blockage, nasal discharge, sneezing, nasal itching, and postnasal drainage. There were no significant differences identified between treatments for nasal discomfort, nasal resistance, or eye symptoms.
Our search identified eight additional studies that were not included in the Weiner meta-analysis. Seven of the studies favored intranasal corticosteroids over antihistamines both with respect to improvement in global nasal symptoms as well as most individual nasal symptoms. One study showed better symptom improvement with cetirizine alone over fluticasone alone. Thus, the overwhelming majority of studies show very clear benefits for the use of intranasal corticosteroids over either sedating or nonsedating antihistamines for relief of symptoms of nasal allergy. These results are similar for seasonal allergic rhinitis and perennial allergic rhinitis.
No RCTs were identified directly comparing immunotherapy with antihistamines in the treatment of seasonal and/or perennial allergic rhinitis. Immunotherapy is generally considered a long-term disease modifying treatment measure requiring months to years of treatment whereas antihistamines are often used for immediate symptom relief. Therefore direct comparisons with respect to effectiveness/efficacy are not likely to be undertaken.
For reasons similar to those above, no RCTs were identified which directly compared immunotherapy with intranasal corticosteroids in the treatment of seasonal and/or perennial allergic rhinitis.
With respect to symptom alleviation in allergic (seasonal) rhinitis, study results indicate no consistent benefit of sedating antihistamines over nonsedating antihistamines. In the eight randomized controlled clinical trials comparing sedating and nonsedating antihistamines in the treatment of seasonal allergic rhinitis, approximately equivalent numbers of patients seemed to benefit in terms of symptom relief from nonsedating antihistamines as from sedating antihistamines, though the side effect profile favors nonsedating antihistamines. Similar observations were seen with perennial allergic rhinitis except perhaps for a tendency to favor sedating antihistamines. The benefits were seen across a range of symptoms with no specific symptom appearing to be better improved by one class of treatment or the other.
Studies provide strong support for the beneficial effect of cromoglycate in the management of both seasonal and perennial allergic rhinitis. Eighteen studies (14/18 studies of seasonal allergic rhinitis and 4/11 studies of perennial allergic rhinitis) included documentation of patient preference or patient willingness to use the drug in the future. In 17 studies there was a clear-cut preference for the active ingredient (cromoglycate). Cromoglycate seems to have higher efficacy in seasonal allergic rhinitis than it does in perennial allergic rhinitis. In those studies that looked at different dosing regimens, higher doses (including higher frequency of dosing) were more effective.
Two clinical trials were identified looking 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 documented no significant differences between dosages of ipratropium but significant reduction in rhinorrhea and postnasal drip.
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 analyzed. However, a recent study (Skoner, Rachelefsky, Meltzer et al, 2000) reported 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. Agents with less systemic bio-availability may be devoid of these risks (Allen, 2000).
No major adverse events were reported in studies of cromolyn; minor reported side-effects included a high frequency of nasal irritation, headache, and nasal congestion.
We found no data to address this question. None of the studies categorized patients by disease severity or concurrent disease when addressing either efficacy or safety.
Two relevant meta-analyses were identified in the published literature. The meta-analysis of randomized controlled clinical trials comparing the use of nasal corticosteroids and antihistamines in the management of allergic rhinitis has been described above (Weiner, Abramson, and Puy, 1998). It shows a strong tendency to significantly greater improvement in all symptoms of allergic rhinitis by use of nasal corticosteroids when compared to either sedating or nonsedating antihistamines.
In a recent meta-analysis of specific allergen immunotherapy in the management of allergic rhinitis, Ross, Nelson, and Finegold (2000) document significant benefit for this therapy in the management of allergic rhinitis. Benefit is seen both with respect to symptom control and symptom medication usage. No other meta-analysis of interest was identified in this analysis.
As our understanding of allergic rhinitis and asthma is increasing, it is becoming clear that the pathophysiology of the two diseases is very similar. The inflammation seen in the tissues is of similar type in both conditions and many of the inflammatory mediators appear to be similar. Furthermore, in addition to the high frequency of concurrence of these diseases in individual patients, there is now evidence of measurable abnormalities in the airways of patients without clinical manifestations of asthma who suffer with allergic rhinitis. Thus, subclinical asthma appears to be identifiable in patients with allergic rhinitis.
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. A small number of prospective cohort studies (Anderson, Pottier, and Strachan, 1992; Settipane, Hagy, and Settipane, 1994) have been performed and demonstrate an increased likelihood of developing asthma over time in patients with allergic rhinitis.
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 link between these two diseases and an ability to impact certain characteristics of asthma by use of nasal corticosteroids in treatment of allergic rhinitis. Conventional doses of cetirizine, loratadine and oral decongestants have been reported to improve asthma symptoms and pulmonary function in patients with allergic rhinitis.
The link between allergic rhinitis and rhinosinusitis is known. Cross-sectional studies have shown an increased prevalence of acute and chronic bacterial sinusitis amongst allergic rhinitis patients. Similarly, there is an increased prevalence of atopy and allergic rhinitis amongst 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 is required. We identified no studies meeting these criteria in our literature search.
A paucity of rigorous data was identified within the existing published literature on allergic rhinitis. The lack of relevant high-quality evidence required that nearly every key question be answered on the basis of suboptimal or incomplete data.
Studies that have focused on nonallergic rhinitis have arrived at this diagnosis by exclusion of allergic diseases (conventional allergy skin testing and/or RAST). There is no specific diagnostic test for nonallergic rhinitis. Until the mechanisms underlying vasomotor rhinitis have been studied further, it is unlikely that a diagnostic test will be developed. The minimum amount of testing required to differentiate between these two conditions remains to be determined. Important questions needing to be addressed include: Does one need a full panel of inhalant aeroallergen skin testing? If so, how big does this panel need to be, and should it vary by geographic region? Might it be feasible to combine groups of similar allergens as a screening panel? For example, a grouping covering the important indoor allergens such as house dust mites, cockroach, cat allergens, and dog allergens; a grouping covering the dominant springtime outdoor aeroallergens (representative local tree and grass pollen species); a grouping covering the dominant outdoor fall aeroallergens (ragweed and other weed pollens); and a grouping covering a mixture of mold spores might prove informative and useful as a screening panel. A similar approach might be applicable to RAST, thus decreasing the number of individual tests (and therefore costs) required. It would be valuable to investigate whether simpler laboratory tests such as measurement of total serum IgE or total eosinophil count might be useful in diagnosing or excluding allergic rhinitis.
One of the major advantages of determining whether allergens are responsible for the patient's condition relates to the benefit that would accrue to the patient from specific allergen avoidance through environmental modification. It would be useful to investigate whether recommendation or implementation of standard measures to minimize exposure to indoor aeroallergens such as house dust mites, pet allergens, and cockroach might be cost effective in the management of chronic rhinitis even in the absence of differentiation between allergic and nonallergic rhinitis and even without determining a patients precise allergic sensitivities.
It is not infrequent to encounter patients who claim to derive relief of symptoms of nonallergic rhinitis from use of antihistamines, and azelastine (an H1 antihistamine) is effective for treatment in vasomotor rhinitis. Since there is no evidence that histamine release is involved in the symptoms of nonallergic rhinitis, it is possible that the antihistamines are helping by improvement of rhinorrhea due to their anticholinergic effects, or by some other, as yet unidentified mechanism. This potential benefit is clearly worthy of further study. It is also possible, since many over-the-counter antihistamine preparations in fact are combined preparations that include nasoactive oral agents, that nasal decongestion provided by this agent is the basis of the symptom relief reported by the patients. These possibilities should be teased out by performing specific studies looking at the role of antihistamines in the management of nonallergic rhinitis. If antihistamines are indeed useful in treatment of nonallergic rhinitis then the need to differentiate between allergic and nonallergic rhinitis would be lessened.
Many of the newer or second-generation antihistamines have insignificant anticholinergic properties. Studies of these agents may help differentiate any benefit from true antihistaminic activity from the benefit associated with the drying provided by anticholinergic mechanisms. Additionally, a new class of antihistamine agents known as H3 receptor antagonists has the potential to offer significant decongestant effects by inhibiting presynaptic mediator release in the nasal tissues, when used in association with an H1 receptor antagonist. Such an agent may offer the benefit of decongestion without the undesirable side-effects such as hypertension and agitation often associated with the vasoactive decongestants (McLeod, Mingo, Herczku, et al., 1999).
Further studies of the role of nasal corticosteroids in nonallergic rhinitis are necessary. Many physicians probably use nasal corticosteroids as a therapeutic trial in the management of nonallergic rhinitis but few studies exist in the published literature documenting that this is a helpful strategy. For reasons similar to those stated for antihistamines, if nasal corticosteroids can be documented to be helpful in nonallergic rhinitis, the need to differentiate allergic from nonallergic rhinitis may be lessened. It might be worth determining how widespread the use of nasal corticosteroids is in patients with nonallergic rhinitis amongst practitioners and to evaluate whether there is any downside to their use.
The potential benefit of cromoglycate in nonallergic rhinitis warrants further study. It is now an over-the-counter preparation with minimal side-effects and two studies have shown benefit for cromoglycate in nonallergic rhinitis. The mechanism of action of this medication is poorly understood as are the mechanisms underlying a majority of cases of nonallergic rhinitis. Accordingly, this may prove a fruitful line of investigation both with respect to disease mechanisms and development of new therapeutics.
Allergen avoidance, after specific diagnostic testing to identify the specific allergic sensitivities is a well-founded treatment recommendation, routinely employed as the first step in the management of allergic rhinitis. Comparative prospective studies would be useful to determine whether, at least in the first instance, empiric prescription with antihistamines or nasal corticosteroids is of value in allergic rhinitis and whether only the more "severe" cases need more specific evaluation as to which allergic sensitivities are present so that allergen avoidance strategies can be recommended. Alternatively, since recommended allergen avoidance measures frequently revolve around modification of the indoor living environment to decrease exposure to house dust mites, cat and dog allergens, and possibly molds, should these recommendations be automatic in patients with allergic rhinitis? Might that approach obviate the need for diagnostic testing in a substantial proportion of patients?
The increasing recognition of the close relationship between the pathophysiology of allergic rhinitis and epidemiological data is very important. Studies to accurately determine whether interventions for allergic rhinitis can have preventive effects for asthma are urgently needed. Such studies will, of necessity, have to be prospective, large in number, and long-term. Since mortality and morbidity from asthma are increasing (especially in urban populations) despite newer pharmacologic treatment agents - such an approach assumes strong imperative.
Our evidence review indicates that many drug interventions are effective in decreasing symptoms, yet data on individual variation in preferences for, responses to, and costs of different therapies are limited. Drug interactions require clarification. A host of complementary therapies are now employed in the treatment of nonallergic rhinitis, but with little rigorous testing of their efficacy.
The low numbers (or absence) of studies that address a variety of clinically meaningful questions may reflect that to date, many drug trials are efficacy trials conducted for purposes of FDA approval of a new pharmaceutical product or post marketing comparisons with competitive products. Postmarketing trials may enroll the minimum number of subjects to establish efficacy, for example, by showing equivalence between a new preparation and an established, approved one. If a product has no commercial potential (e.g., because it is no longer patented) funding to support its investigation will likely suffer.
The challenge for the healthcare research community transcends the biomedical dimension of allergic rhinitis management to encompass its societal and human aspects. Research studies must address prospectively and in increasing depth issues of importance to patients and clinicians (patient preferences, satisfaction with care, the proportion who improve with care, treatment side-effects), providers and payers (costs), and researchers (optimal trial design and reporting). Patients and their families must be invited to help formulate research priorities and to advise in the design of trials themselves, such as suggesting outcomes of interest and novel ways to assess them, e.g., via the Internet (Silberg, Lundberg, and Musacchio, 1997).
Standards for allergic and nonallergic rhinitis treatment trials 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, tests, outcome measures, and circumstances of testing found in the RCTs. This situation makes synthesizing the research results difficult. Reducing this heterogeneity by implementing a set of standardized research variables would greatly assist in comparing studies.
The characteristics of patients enrolled in studies need to be clearly defined. This is critical to ensure internal validity and to allow for study comparisons, data analyses, and in applying the results to clinical practice. Standardization of research variables would also aid in identifying the best strategies for detection of patients with allergic or nonallergic rhinitis.
EPC/Project Director
Joseph Lau, MD
Assistant Project Director
Caroline McFadden, MD
Primary Technical Expert
Aidan Long, MD
Project Manager
Deirdre DeVine, M Litt
Statistician
Norma Terrin, PhD
Research Associate
Priscilla Chew, MPH
Joseph Lau, MD
Project Director
Division of Clinical Care Research
New England Medical Center
Boston, Massachusetts
Aidan Long, MD
Primary Technical Expert
Director of Allergy
Massachusetts General Hospital
Boston, MA
Harry Handelsman, DO
Medical Officer
Center for Practice and Technology Assessment
Agency for Healthcare Research and Quality
Rockville, MD
William Berger, MD, MBA
American College of Allergy, Asthma and Immunology
Mission Viejo Medical Center
Mission Viejo, CA
John W. Georgitis, MD, FAAAAI
American Academy of Allergy, Asthma and Immunology
Wake Forest University School of Medicine
Winston-Salem, NC
Barbara Yawn, MD, MSc
American Academy of Family Physicians
Olmsted Medical Center
Rochester, MN
The American Academy of Family Physicians, partner organization for the evidence report, nominated individuals to participate in the peer review of the report, as did the other organizations of the EPC Technical Expert Panel, the American College of Allergy, Asthma and Immunology, and the American Academy of Allergy, Asthma and Immunology.
We are grateful to the peer reviewers for generously offering their time and knowledge.
American Academy of Family Physicians
Doug Campos-Outcalt, MD
Stuart Stoloff, MD
American College of Allergy, Asthma & Immunology
Daniel Ein, MD
Richard G. Gower, MD
American Academy of Allergy, Asthma & Immunology
Harold S. Nelson, MD, FAAAAI
Michael J. Schumacher, MD
FAAAAI
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