Assessment of disease control in allergic rhinitisPascal Demoly, 1 Moises A Calderon,2 Thomas Casale,3 Glenis Scadding,4 Isabella Annesi-Maesano,5 Jean-Jacques Braun,6 Bertrand Delaisi,7 Thierry Haddad,8 Olivier Malard,9 Florence Trébuchon,10 and Elie Serrano11

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AbstractThe Allergic Rhinitis and its Impact on Asthma (ARIA) initiative has had a significant impact, by raising awareness of allergic rhinitis (AR) and improving the diagnosis and treatment of AR sufferers. ARIA classifies the severity of AR as "mild" or "moderate/severe" on the basis of "yes"/"no" answers to four questions. This two-point classification has been criticized as providing little guidance on patient management; patients with "mild" AR are unlikely to consult a physician, whereas the group of patients with "moderate/severe" seen by specialists is heterogeneous. These perceived shortcomings have prompted attempts to improve the ARIA classification or, by analogy with the Global Initiative for Asthma (GINA), adopt approaches based on "disease control" in AR. Even though "disease severity", "disease control" and "responsiveness to treatment" are different (albeit related) metrics, they are not mutually exclusive. Currently, there is no single, accepted definition, but we propose that "disease control" in AR can combine (i) measurements of the severity and/or frequency of daily or nocturnal symptoms, (ii) impairments in social, physical, professional and educational activities, (iii) respiratory function monitoring and (iv) exacerbations (e.g. unscheduled medical consultations and rescue medication use). Although control-based classifications have a number of limitations (e.g. their dependence on treatment compliance and the patient's psychological status), these instruments could be used as an adjunct to the ARIA severity classification and regional practice parameters. Here, we assess the strengths and weaknesses of the current two-level ARIA classification, analyze published proposals for its modification and review the literature on instruments that measure AR control. We conclude that there is a need for research in which severity is compared with control in terms of their effects on patient management.

Keywords: Allergic rhinitis, Disease control, Disease severity, Classification, Questionnaire, ARIA, GINA

Allergic rhinitis (AR) is a highly prevalent, chronic disease, with rates of up to 50% in some populations [1,2]. Furthermore, the prevalence is increasing in many "westernized" countries [3]. Its disease burden is considerable - with negative impacts on sleep, mood, social functioning, work/school performance and health-related quality of life [4-6] and can no longer be neglected by healthcare payers since this burden is associated with direct health resource costs and indirect socio-economic costs (e.g. absenteeism and loss of productivity) [7]. Furthermore, the detrimental effects of AR on established asthma and the link between AR and the subsequent development of asthma are well established [8]. Paradoxically, this disease burden tends to be

underestimated by both patients and physicians [9]. In Europe, over half of AR sufferers do not seek medical advice [10]. Treated patients also report poor levels of satisfaction, with a constant search for a combination of medications that "works" by reducing their nasal symptoms [11].

Challenged by these patient needs and the lack of awareness among patients and physicians, a number of global, regional and local initiatives and guidelines for improving the diagnosis, treatment and follow-up of AR sufferers have been developed [12]. One of the key initiatives relates to the output of the 1999 Allergic Rhinitis and its Impact on Asthma (ARIA) workshop (organized by the World Health Organization), published in 2001 and updated in 2008 and 2010 [13-15]. To aid the implementation of a stepwise approach to patient management, ARIA introduced a patient classification based on the AR symptoms' time patterns ("intermittent" vs. "persistent") and severity ("mild" vs. "moderate/severe"). Although the ARIA severity classification has been validated in primary care patients [2,16], surveys have found that both primary care physicians (PCPs) and specialists are not necessarily aware of this tool [17]. Lastly, regulatory authorities tend to consider that AR cannot truly be severe and/or uncontrollable.

By analogy with trends in the management of asthma following the introduction of the Global Initiative for Asthma (GINA) guidelines [18]), there is a general, WHO-endorsed trend towards the generalization of the "control" approach to other conditions, including AR, chronic rhinosinusitis, chronic urticaria and atopic dermatitis [19]. As discussed below, there is no single definition of "disease control", since the variables taken into account and the severity thresholds corresponding to "relief" vary from one tool to another. However, by analogy with GINA in asthma, measurements of "control" in AR can combine (i) measurements of daily or nocturnal symptoms, (ii) impairments in social, physical, professional or educational activities, (iii) respiratory function monitoring and (iv) events related to exacerbations (such as medical consultations and the need for rescue medication). Hence, long-term, stable disease control equates to minimal symptoms, no limitations in activities, minimal use of rescue medications and infrequent exacerbations.

The objective of the present work was to (i) assess the strengths and weaknesses of the ARIA classification in terms of guiding the treatment of AR, (ii) review published proposals for the modification of ARIA and (iii) review instruments for determining disease control in AR. We searched MEDLINE, Embase and the Cochrane Library up until May 2012 using logical combinations of the following terms (in English only): allerg*; rhinit*; ARIA; "Allergic Rhinitis and its Impact on Asthma"; control; questionnaire; rating; scale; score.

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Strengths and weaknesses of the current ARIA severity classificationThe ARIA classification was clearly a great step forward in 2001, since it acknowledged the impact of a disease that was often qualified as “trivial" and emphasized the need to assess patient needs and treat accordingly. The ARIA "mild" vs. "moderate/severe" classification [13-15] has a number of strengths and weaknesses (Table 1). It has the advantage of being very simple to

administer, since it is based on "yes"/"no" answers to each of the following statements: "My symptoms disturb my sleep", "My symptoms restrict my daily activities (sports, leisure, etc.)", "My symptoms restrict my participation in school or work" and "My symptoms are troublesome". In ARIA, "mild" AR corresponds to "no" answers to all four questions, whereas the presence of a "yes" for one or more items corresponds to "moderate/severe" AR. The ARIA duration and severity classifications have been implemented in several countries and patient populations. For example, the ADRIAL and PEDRIAL cohort studies of adult and paediatric AR patients in Spain [20,21] found that symptom, Rhinitis Quality of Life Questionnaire (RQLQ) and visual analogue scale (VAS) scores were significantly higher in "moderate/severe" than in "mild" AR. In France, Bousquet et al. studied 3052 patients consulting PCPs and who were classified according to the ARIA classification (mild intermittent: 11%; mild persistent: 8%; moderate/severe intermittent: 35%; moderate/severe persistent: 46%). All patients were scored for the RQLQ, the Jenkins sleep questionnaire and the Allergy-Specific Work Productivity and Activity Impairment questionnaire [22]. Impairments were correlated more strongly with severity than duration. Eighty per cent of the patients with moderate-to-severe AR reported impaired activities, as opposed to only 40% of the patients classified as having mild AR.

Table 1Strengths and weaknesses of the two-level ARIA severity classification ("mild" vs. "moderate/severe") for AR

Levels of awareness and application of the ARIA severity classification are less than satisfactory. In a study of 943 French PCPs and 277 ear, nose and throat (ENT) specialists, Demoly et al. found that only about 54% of the physicians were aware of the ARIA classification. Over 90% of these actually applied the classification in practice - although there were significant differences between PCPs and ENT specialists [17]. Furthermore, knowledge of the ARIA classification by PCPs did not appear to influence the use of H1-antihistamines (H1As) and/or intranasal corticosteroids (ICSs) as a function of the patient's disease severity [17]. In another cohort study performed in France [23], researchers found that ARIA severity did not significantly influence medication prescription. Although ARIA suggests that patients with mild and intermittent AR should receive H1As and those with moderate/severe and persistent AR should receive ICSs, Ramirez et al.'s analysis of 3026 patients with intermittent AR and 3507 patients with persistent AR (enrolled by 1346 practitioners) revealed that immediate prescription of H1A+ICS combination therapy was surprisingly frequent [23].

For AR patients seen by specialists, the "mild" vs. "moderate/severe" distinction has less value since by definition, a patient with "mild" AR is not bothered by his/her symptoms and is unlikely to consult a specialist. In Valovirta et al.'s survey of patients aged 16 and over [9], 87% of those with persistent conditions and 79% of those with intermittent conditions reported that at least one

daily activity was moderately or severely affected “all the time”. Similarly, Van Hoecke et al. observed that 89.3% of patients consulting PCPs in Belgium were classified as "moderate-severe" [24], as was the case for 92.2% of the patients in the above-mentioned French cohort [17,25].

However, “moderate-severe” AR is extremely broad (with as few as one or all four ARIA items impaired) and encompasses a highly heterogeneous group of patients. It includes patients with severe chronic upper airway disease (SCUAD) [26], candidates for allergen specific immunotherapy or nasal obstruction surgery and patients with severe disease in the absence of treatment but who respond well to ICSs or even H1As alone. As such, classification of a patient as suffering from “moderate-severe” AR is of little help in guiding the physician's treatment recommendations. In this respect, it has even been suggested that term "moderate/severe" should be replaced by "severe" alone [22]. Lastly, the ARIA classification does not take account of past and present treatment; this is an important shortcoming, since most AR patients seen for the first time by a physician will have already taken prescription and/or over-the-counter medications for their condition. In summary, consideration of the ARIA classification's particular features has highlighted unmet needs in the routine clinical management of AR.

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Attempts to refine, improve or simplify the ARIA classificationSince the publication of ARIA's initial work in 2001, several attempts have been made to refine the "mild" vs. "moderate/severe" classification. In 2007, Valero et al. suggested drawing a distinction between 1 to 3 affected ARIA items on one hand and 4 affected items on the other, with the assignment of "moderate" and "severe" disease grades to these respective situations [27]. In a study of over a thousand treatment-naïve patients, classification as "mild", "moderate" or "severe" was correlated with the disease-specific "Cuestionario ESPañol de Calidad de Vida en RINiTis" (ESPRINT-15) quality of life score [28].

In a study in Belgium, Van Hoecke et al. suggested the use of just two ARIA questions (one question on sleep disturbance and one on impairment in daily life) and the introduction of an additional, "moderate" category [24]. Two "no" replies equated to "mild" AR, one "yes" and one "no" equated to "moderate" AR and two "yes" replies equated to "severe" AR [24]. However, in a cohort of 5140 patients in France classified as having mild (n=357, 7.0%), moderate (n=2498, 48.6%) or severe AR (n=2285, 44.4%) according to Van Hoecke et al.'s suggestion, Demoly et al. found that "no clear clinically relevant trends were observed that could support the need for a distinction between mild, moderate and severe patients" [29]. In response to these proposals to classify AR severity as “mild”, “moderate” and “severe”, the ARIA 2008 authors stated that this "makes it more complex for the practising physician without bringing significant improvement to the patient since this more complex classification does not translate to a difference in therapeutic options" [14].

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Visual analogue scalesVisual analogue scales have been suggested as simple tools for assessing AR severity. Firstly, Bousquet et al. [30] found that a 0 to 10 cm VAS score and the RQLQ score were significantly correlated (rho = 0.46; p <0.0001) and that a patient with a VAS score below 5 cm could be classified as having "mild" AR (negative predictive value: 93.5%), whereas a VAS score over 6 cm was equated with "moderate/severe" AR (positive predictive value: 73.6%). Indeed, the ARIA 2008 guidelines subsequently included a classification in which "mild" AR = 0–3 cm, "moderate" AR = 3.1–7 cm and "severe" AR = 7.1–10 cm. Secondly, the United States' Joint Task Force on Practice Parameters [31] suggested that six VASs (sneezing, runny nose, congestion, itchy nose, postnasal drip and total nasal symptoms) could be used. However, the Task Force's 2003 publication did not present any results on application of these VASs and the validation status of this instrument is uncertain. Thirdly, two of the present authors (PD and IAM) and colleagues compared a VAS severity score with a numerical severity score (both assessed by a physician) in a sample of 36,000 patients with diagnosed, non-complicated, untreated, intermittent AR [32]. Although the two scores were correlated, the absolute values differed and 23.86% of the patients were classified as "severe" according to one scale but not the other.

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Instruments for assessing disease control in allergic rhinitisDisease control is now being considered as an alternative to disease severity in the management of patients with respiratory disease. Indeed, the assessment of disease control in AR was briefly mentioned in the ARIA 2008 update [14], since "as for asthma, one of the problems to consider is to replace severity by control". However, the ARIA authors noted that, at the time the update was drafted, "sufficient data are not yet available" and that "control questionnaires or methods are still undergoing validation" [14]. Since then, however, a number of AR control questionnaires have been built and validated according to the ideal methodological sequence [33]. These questionnaires are summarized in Table 2.

Table 2A comparison of three published allergic rhinitis control questionnaires

The Control of Allergic Rhinitis and Asthma Test (CARAT) was initially developed by Nogueira-Silva et al. in Portuguese [34]. After a literature search, Nogueira-Silva et al. included 17 questions in a questionnaire with a Likert scale. The reference period was four weeks – long

enough to monitor control over time but short enough to be unaffected by recall bias. A ten-question version of CARAT (CARAT10) was subsequently validated in a cross-sectional study of 193 adults by Fonseca et al. [35]. The range of possible scores for CARAT10 is 0–30, 0 being the complete absence of control. The CARAT10 served as a guide to patient management, since the mean [95% confidence interval] scores associated with the intensification, maintenance and reduction of treatment were 15 [13.6-16.5], 21 [19.4-21.9] and 24 [21.4-26.6], respectively.]. Most recently, Fonseca et al. investigated the CARAT in 62 patients included at 4 outpatient clinics in Portugal [36]. At two visits 4 to 6 weeks apart, a total of 51 patients (aged between 18 and 70) completed the CARAT10, the Asthma Control Questionnaire [37], three VASs (on airways symptoms, bronchial/pulmonary symptoms and nasal symptoms) and an overall self-assessment of control. Lung function was also tested. The test-retest reliability (intra-class correlation coefficient) was 0.82. A significant change in the CARAT10 score was observed in clinically unstable patients. In terms of the change over time in the CARAT10 score, the correlation ranged from 0.49–0.65 for the ACQ5 and VAS symptom scores and from 0.31 to 0.41 for the physician's assessment of control [36].

Nathan et al. developed a 26-item Rhinitis Control Assessment Test (RCAT) and refined it to 6 items. After testing the RCAT in 410 AR patients [38,39], six of the 26 initial items (nasal congestion, sneezing, and watery eyes, sleep interference, activity avoidance and self-assessed control) were most predictive (p <0.001 for all) of the allergist’s overall rating of rhinitis symptom control.

By working with a multidisciplinary group associating allergists, pulmonologists, ENT physicians and methodologists, Demoly et al. developed a five-item, self-assessment Allergic Rhinitis Control Test (ARCT) [40] with similarities to the Asthma Control Test (ACT) [41]. Two ACT questions (on rescue medication and overall assessment of the disease) were incorporated into the ARCT. The questionnaire was validated by testing in 902 patients (selected by 411 PCPs and allergists) before treatment and two weeks after treatment. The score at inclusion correlated significantly (p<0.0001) with the patient's overall clinical status and the impact of AR on social and sporting activities. A significant (p<0.0001) increase in the score was observed after two weeks of treatment (from 14.9±4.0 at inclusion to 21.5±2.9 after treatment). Using a receiver operating characteristic curve, a score of 20 was found to be the optimal cut-off for poor vs. well-controlled rhinitis (sensitivity: 67%; specificity: 82%; negative predictive value: 32%; positive predictive value: 95%).

The "Allergy-Control-SCORE"TM[42] measures (i) the severity of 10 nasal and non-nasal symptoms on a 4-point scale) and (ii) medication use (out of a catalogue of 745 different medications) and combines the two metrics with equal weighting. In a study of 81 patients with allergic rhinoconjunctivitis and 40 healthy controls, the Allergy-Control-SCORE was significantly correlated with the global assessment of allergy severity, the RQLQ score and the number of medical consultations due to allergy within the previous year. In our opinion, "Allergy-Control-SCORE" is something of a misnomer because this approach is conventionally referred to as a "combined score" (i.e. a combination of a symptom score and a medication score) and has been extensively used in clinical trials for many years [43].

Lastly, Scadding et al. took a different approach by asking experts to complete an online survey about what they regarded as rhinitis control in relation to the seven questions in Juniper's mini-RQLQ [44]. All the respondents considered that more than “somewhat troubled” was unacceptable. Indeed, most of the experts defined control as being “hardly troubled at all” by each symptom.

Unfortunately, head-to-head comparisons of these various control-based tools have not been reported.

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Discussion

Disease severity vs. disease control

Although "disease severity", "disease control" and "responsiveness to treatment" are different (albeit related) metrics, they are not mutually exclusive [45]. Disease severity can be defined as a loss of physiological function caused by the disease process. Both severity and control can be measured in a multitude of ways, with both objective and subjective measurements and patient-reported vs. physician-reported outcomes. Patient-reported metrics are growing in importance in clinical research and, increasingly, in patient care [46], although there is debate over whether the physician or the patient is best placed to judge disease control [47]. There is a need for research in which severity is compared with control in terms of the respective effects on patient management.

Conceivably, some cases of severe disease might respond well to treatment (i.e. good control), whereas some cases of mild disease might not (i.e. poor control). Likewise, a totally controlled patient taking an H1A and an ICS will probably still have severe underlying disease [19]. Furthermore, poor disease control may be related to poor treatment compliance and psychosocial factors rather than high disease activity. Mild disease may be a problem for some patients but not for others. Conversely, severe disease may bother some patients far less than others.

Severity can be measured in treatment-naïve patients but, by definition, the concept of disease control is only applicable in treated patients. Hence, conventional measurements of severity will continue to be essential in treatment-naïve patients consulting for the first time or in undiagnosed AR sufferers in the general population. In this respect, the VAS appears to be a valid shortcut for the definition of disease severity. However, a one-dimensional scale cannot encompass the complex spectrum of parameters involved in disease control (i.e. impairments in everyday life, respiratory function and exacerbations, in addition to symptom severity).

Control-based classifications have a number of limitations. Some are related to the underlying concept of measuring disease control over the previous weeks, since factors such as treatment compliance and the patient's psychological status will have an effect on perceived disease control – even when intrinsic disease activity is constant. It is not yet clear whether AR control varies significantly as a function of the disease-inducing allergen. For example, it is possible that the achievement of control in patients with persistent AR induced by house dust mites is very

different from that in patients with AR induced by grass pollen. This is a complex area requiring further research.

Lastly, the questionnaires used to evaluate AR control have been developed and validated in adolescents and adults. However, by analogy with tools such as the Childhood Asthma Control Test [48], extension to children with AR can be envisaged.

The potential impact of disease control instruments on clinical practice

The ARIA guidelines state that "treatment should be tailored according to the severity of the disease, comorbidities, treatment availability and affordability and patients’ preference". Two recent papers co-authored by ARIA indicate that (i) disease control is being considered for future initiatives [49] and (ii) methods for measuring severity and control in allergic disease must be uniform [49]. The adoption of control-based approaches in AR is likely to modify the physician-patient relationship. The CARAT, RCAT and ARCT are multi-item questionnaires that require the patient to provide a fair amount of information on his/her recent condition. However, since control is largely a patient-led concept, remote measurements (by 'phone or over the Internet) could conceivably reduce the frequency of face-to-face consultations. Nevertheless, as noted by Glasziou et al. [50], the benefits of monitoring the response to treatment, detecting adverse effects and gauging the need to adjust treatment must be balanced against inconvenience, cost and the potential impact of false positives and false negatives of disease control. Measurements of control must therefore be reproducible, quick and easy to perform in routine practice and should focus on the disease's impact in everyday life. For example, one could consider an approach in which a patient's degree of disease control is simply equated to the "strength" of the medication (i.e. therapeutic pressure) that he/she has to take in order to gain sufficient relief from his/her symptoms.

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ConclusionWhile the ARIA classification of the severity of AR is useful, it is not an optimal guide for making everyday patient management decisions, especially in patients already on therapy. Experience in asthma suggests that there are good reasons to consider measuring control on a routine basis in AR, as a complement to ARIA's severity-based approach. There is a need to compare existing tools and perhaps develop new ones. Regardless of the details of control-based classifications in AR, the key challenge for any instrument will be to achieve high levels of physician awareness, uptake and application - which should ultimately lead to better patient outcomes.

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Abbreviations

ACS: Allergy-Control-SCORE; AR: Allergic rhinitis; ARC: Allergic Rhinitis Control; ARCT: Allergic Rhinitis Control Test; ARIA: Allergic Rhinitis and its Impact on Asthma; CARAT: Control of Allergic Rhinitis and Asthma Test; ENT: Ear, nose and throat; GINA: Global Initiative for Asthma; H1A: H1-antihistamine; ICS: Intranasal corticosteroid; PCP: Primary care physician; RCAT: Rhinitis Control Assessment Test; RQLQ: Rhinitis Quality of Life Questionnaire; VAS: Visual analogue scale.

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Competing interestsPascal Demoly is a consultant and a speaker for Stallergenes, ALK and Chiesi and was a speaker for Merck, Astra Zeneca, Menarini and GlaxoSmithKline in 2010–2012. Moises Calderon has received consulting fees, honoraria for lectures and/or research funding from ALK-Abello, Merck, Stallergenes and Allergopharma. Glenis Scadding has received consulting fees, honoraria for lectures and/or research funding from ALK-Abello, GSK, Meda, Merck and Stallergenes. Thomas Casale has received consulting fees from Stallergenes and has been an investigator on grants awarded to Creighton University by Stallergenes and Schering-Plough-MSD. This work was supported by an educational grant from Stallergenes.

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Authors’ contributionsPD, MC, TC, GS, IAM, JJB, BD, TH, OM, FT and ES all made substantial contributions to the (i) the conception and design of the disease control classification and (ii) the identification and review of relevant literature on ARIA and published proposals for modification. Likewise, PD, MC, TC, GS, IAM, JJB, BD, TH, OM, FT and ES were all involved in drafting the manuscript and/or revising it critically for important intellectual content. All the authors have given final approval of the version to be published.

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AcknowledgmentsWe thank David Fraser PhD for medical writing support.

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26. Bousquet J, Bachert C, Canonica GW, Casale TB, Cruz AA, Lockey RJ, Zuberbier T. Extended Global Allergy and Asthma European Network, World Allergy Organization and Allergic Rhinitis and its Impact on Asthma Study Group. Unmet needs in severe chronic upper airway disease (SCUAD) J Allergy Clin Immunol. 2009;3:428–433. doi: 10.1016/j.jaci.2009.06.027. [PubMed] [Cross Ref]

27. Valero A, Ferrer M, Sastre J, Navarro AM, Monclús L, Martí-Guadaño E, Herdman M, Dávila I, Del Cuvillo A, Colás C, Baró E, Antépara I, Alonso J, Mullol J. A new criterion by which to discriminate between patients with moderate allergic rhinitis and patients with severe allergic rhinitis based on the Allergic Rhinitis and its Impact on Asthma severity items. J Allergy Clin Immunol. 2007;3:359–365. doi: 10.1016/j.jaci.2007.04.006. [PubMed] [Cross Ref]

28. Valero A, Munoz-Cano R, Sastre J, Navarro AM, Marti-Guadano E, Davila I, Del Cuvillo A, Colas C, Antepara I, Izquierdo I, Mullol J. The impact of allergic rhinitis on symptoms, and quality of life using the new criterion of ARIA severity. Rhinology. 2012;3:33–36. [PubMed]

29. Demoly P, Urbinelli R, Allaert FA, Bousquet PJ. Should we modify the allergic rhinitis and its impact on asthma dichotomic classification of severity? Allergy. 2010;3:1488–1490. doi: 10.1111/j.1398-9995.2010.02374.x. [PubMed] [Cross Ref]

30. Bousquet PJ, Combescure C, Neukirch F, Klossek JM, Mechin H, Daures JP, Bousquet J. Visual analog scales can assess the severity of rhinitis graded according to ARIA guidelines. Allergy. 2007;3:367–372. doi: 10.1111/j.1398-9995.2006.01276.x. [PubMed] [Cross Ref]

31. Spector SL, Nicklas RA, Chapman JA, Bernstein IL, Berger WE, Blessing-Moore J, Dykewicz MS, Fineman SM, Lee RE, Li JT, Portnoy JM, Schuller DE, Lang D, Tilles SA. Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma, and Immunology, American College of Allergy, Asthma, and Immunology, Joint Council of Allergy, Asthma, and Immunology. Symptom severity assessment of allergic rhinitis:

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32. Rouve S, Didier A, Demoly P, Jankowsky R, Klossek JM, Annesi-Maesano I. Numeric score and visual analog scale in assessing seasonal allergic rhinitis severity. Rhinology. 2010;3:285–291. [PubMed]

33. Farnik M, Pierzchała W. Instrument development and evaluation for patient-related outcomes assessments. Patient Related Outcome Measures. 2012;3:1–7. [PMC free article] [PubMed]

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35. Fonseca JA, Nogueira-Silva L, Morais-Almeida M, Azevedo L, Sa-Sousa A, Branco-Ferreira M, Fernandes L, Bousquet J. Validation of a questionnaire (CARAT10) to assess rhinitis and asthma in patients with asthma. Allergy. 2010;3:1042–1048. doi: 10.1111/j.1398-9995.2009.02310.x. [PubMed] [Cross Ref]

36. Fonseca JA, Nogueira-Silva L, Morais-Almeida M, Sa-Sousa A, Azevedo LF, Ferreira J, Branco-Ferreira M, Rodrigues-Alves R, Bugalho-Almeida A, Bousquet J. Control of Allergic Rhinitis and Asthma Test (CARAT) can be used to assess individual patients over time. Clin Transl Allergy. 2012;3:16. doi: 10.1186/2045-7022-2-16. [PMC free article] [PubMed] [Cross Ref]

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38. Nathan RA, Dalal AA, Stanford RH, Meltzer EO, Schatz M, Derebery J, Mintz M, Thompson MA, Dibenedetti DB. Qualitative Development of the Rhinitis Control Assessment Test (RCAT), an Instrument for Evaluating Rhinitis Symptom Control. Patient. 2010;3:91–99. doi: 10.2165/11318410-000000000-00000. [PubMed] [Cross Ref]

39. Schatz M, Meltzer EO, Nathan R, Derebery MJ, Mintz M, Stanford RH, Dalal AA, Silvey MJ, Kosinski M. Psychometric validation of the rhinitis control assessment test: a brief patient-completed instrument for evaluating rhinitis symptom control. Ann Allergy Asthma Immunol. 2010;3:118–124. doi: 10.1016/j.anai.2009.11.063. [PubMed] [Cross Ref]

40. Demoly P, Jankowski R, Chassany O, Bessah Y, Allaert FA. Validation of a self-questionnaire for assessing the control of allergic rhinitis. Clin Exp Allergy. 2011;3:860–868. doi: 10.1111/j.1365-2222.2011.03734.x. [PubMed] [Cross Ref]

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44. Scadding G, Batten TN, Skinner MA, Dunham KA, Capella A, Calderon M. Identification of the Cut-off Point Between Adequately and Inadequately Controlled rhinoconjunctivitis/rhinitis using the mini-Rhinoconjunctivitis Quality Of Life Questionnaire. Nottingham, UK: Poster presentation at the The British Society for Allergy & Clinical Immunology Annual Conference; 2012.

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Intranasal Corticosteroids in Management of Acute Sinusitis: A Systematic Review and Meta-AnalysisGail Hayward, MBBChir, DPhil, Carl Heneghan, BM, BCH, MA, MRCGP, DPhil, Rafael Perera, MSc, DPhil, and Matthew Thompson, MBChB, MPH, DPhil, MRCGPAuthor information ► Article notes ► Copyright and License information ►This article has been cited by other articles in PMC.

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Abstract

PURPOSE

Acute sinusitis is a common condition in ambulatory care, where it is frequently treated with antibiotics, despite little evidence of their benefit. Intranasal corticosteroids might relieve symptoms; however, evidence for this benefit is currently unclear. We performed a systematic review and meta-analysis of the effects of intranasal corticosteroids on the symptoms of acute sinusitis.

METHODS

We searched MEDLINE, EMBASE, the Cochrane Central register of Controlled Trials (CENTRAL), and Centre for Reviews and Dissemination databases until February 2011 for studies comparing intranasal corticosteroids with placebo in children or adults having clinical symptoms and signs of acute sinusitis or rhinosinusitis in ambulatory settings. We excluded chronic/allergic sinusitis. Two authors independently extracted data and assessed the studies’ methodologic quality.

RESULTS

We included 6 studies having a total of 2,495 patients. In 5 studies, antibiotics were prescribed in addition to corticosteroids or placebo. Intranasal corticosteroids resulted in a significant, small increase in resolution of or improvement in symptoms at days 14 to 21 (risk difference [RD] = 0.08; 95% CI, 0.03–0.13). Analysis of individual symptom scores revealed most consistently significant benefits for facial pain and congestion. Subgroup analysis by time of reported outcomes showed a significant beneficial effect at 21 days (RD = 0.11; 95% CI, 0.06–0.17), but not at 14 to 15 days (RD = 0.05; 95% CI, −0.01 to 0.11). Meta-regression analysis of trials using different doses of mometasone furoate showed a significant dose-response relationship (P=.02).

CONCLUSIONS

Intranasal corticosteroids offer a small therapeutic benefit in acute sinusitis, which may be greater with high doses and with courses of 21 days’ duration. Further trials are needed in antibiotic-naïve patients.

Keywords: corticosteroids, sinusitis, meta-analysis, intranasal administration, inhaled, facial pain, congestionGo to:

INTRODUCTION

Acute sinusitis is a common condition, affecting an estimated 31 million Americans annually.1 The majority of patients seen in primary care for acute sinusitis are prescribed antibiotics,2,3 despite evidence that they provide limited benefit.4–6 The effectiveness of other treatments such as decongestants and antihistamines is largely unknown.7,8 Corticosteroids are effective in reducing symptoms in other upper respiratory tract infections such as croup, sore throat, and infectious mononucleosis, and their anti-inflammatory effects may be helpful for reducing sinus congestion and facilitating drainage in sinusitis.9–12

Currently, it is not clear whether corticosteroids offer significant benefits for patients with acute sinusitis. In particular, there have been no good-quality double-blind randomized controlled trials (RCTs) examining oral corticosteroids in acute sinusitis, even though the oral route is favored for other upper respiratory tract infections. In terms of intranasal steroids, a Cochrane review of 4 RCTs showed a small beneficial effect on improvement of symptoms at 15 to 21 days; however, interpretation was limited by both high heterogeneity and differing outcome measures used in the primary studies.13 A recent large RCT found no difference between intranasal corticosteroids and placebo for sinusitis.14 This trial was not included in the recent Cochrane review.13

Given the conflicting evidence, there is a pressing clinical need to clarify whether intranasal corticosteroids should be prescribed for patients with acute sinusitis. Accordingly, we undertook a systematic review of the most recent evidence to attempt to resolve this question.

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METHODS

Search Strategy and Selection

We included in our meta-analysis RCTs that compared intranasal corticosteroids with placebo in children or adults who had clinical symptoms and signs of acute sinusitis or rhinosinusitis, in outpatient (ambulatory) settings. We excluded studies examining patients with chronic/allergic sinusitis and studies performed exclusively in patient populations selected because of chronic underlying health conditions (eg, immunocompromised patients).

We searched MEDLINE, EMBASE, the Cochrane Library including the Cochrane Central register of Controlled Trials (CENTRAL), the Database of Reviews of Effectiveness (DARE), and the National Health Service Health Economics Database from the beginning of each database until February 2011 using a maximally sensitive strategy.15 Medical Subject Heading (MeSH) terms used included rhinosinusitis, sinusitis, and corticosteroids (including dexamethasone, beta-methasone, prednisone, and all variations of these terms) and viral and bacterial upper respiratory tract pathogens (full search strategy available from authors). Two authors independently reviewed the titles and abstracts of electronic searches, obtaining full-text articles to assess for relevance where necessary. Disagreements were resolved by discussion with a third author. We performed citation searches of all full-text papers retrieved.

Data Extraction and Quality Assessment

Two authors independently assessed the methodologic quality of studies. Quality was assessed using the criteria of allocation concealment, randomization, comparability of groups at baseline, blinding, treatment adherence, and percentage participation. Two authors independently extracted data using an extraction template. In both data extraction and quality assessment, disagreements were documented and resolved by discussion with a third author.

Primary outcomes included the proportion of participants with improvement or complete resolution of symptoms. Secondary outcomes included mean change in symptom scores over 0 to 21 days, adverse events, relapse rates, and days missed from school/work. Where necessary, we used Grab It XP Microsoft Excel software (http://www.datatrendsoftware.com) to extract data from figures.

Data Synthesis and Analysis

For pooled analysis of dichotomous outcomes, we calculated the risk difference (RD), 95% CI, and number needed to treat (NNT). For continuous variables, we used weighted mean difference and 95% CIs. We tested dose response by undertaking a post hoc subgroup analysis according to intranasal corticosteroid dosage. We used meta-regression in Stata (StataCorp, LP) to test subgroup interactions on the outcomes and the I2 statistic to measure the proportion of statistical heterogeneity for each outcome.16 Where no heterogeneity was present, we performed a fixed-effect meta-analysis. Where substantial heterogeneity was detected, we looked for the direction of effect and considered the reasons for this heterogeneity. Where applicable, we used a random-effects analysis or considered not pooling the outcomes and reporting the reasons for this.

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RESULTS

Study Characteristics

We identified 3,257 potentially relevant study records, of which 21 were relevant to acute sinusitis/rhinosinusitis (Figure 1). We excluded 15 of these studies for the following reasons: 5 were abstracts only with no full paper published or available from the authors, 3 were not limited to acute sinusitis, 3 examined oral steroids, 3 did not directly compare steroids and placebo, and 1 examined prevention of acute sinusitis.

Figure 1Flow diagram of search results.

The characteristics of included studies are presented in Table 1. The 6 included studies randomized 2,495 patients recruited from outpatient otorhinolaryngology, emergency medicine, and general practice settings in 3 countries: the United States (4 studies), Turkey (1), and United Kingdom (1). The age range of participants varied: 12 years or older (3 studies); 16 years or older (1); 18 years or older (1); and 15 years or younger (1). The corticosteroids used were budesonide (2 studies), fluticasone propionate (1), and mometasone furoate (3). Two trials compared 2 different doses of mometasone furoate.17,18

Table 1Characteristics of Trials Included in the Meta-Analysis

In addition to intranasal corticosteroids, 5 trials14,18–21 prescribed antibiotics (amoxicillin, co-amoxiclav, or cefuroxime) to patients in both groups. One of these trials19 prescribed intranasal xylometazoline hydrochloride to all participants before administration of the study spray for the first 3 days. Two trials reported outcomes based on computed tomography scans of sinuses.18,21

All 6 included studies demonstrated adequate allocation concealment, blinding, percentage participation, and comparability of groups both at baseline and in provision of care apart from the intervention; however, 3 studies did not report the method of randomization (Table 2). We therefore performed a sensitivity analysis excluding these studies.

Table 2Methodologic Quality of Included Studies

Resolution or Improvement of Symptoms at Days 14 to 21

In 5 RCTs14,17,18,20,21 that assessed resolution or improvement of symptoms at days 14 to 21, intranasal steroids had a modest clinical beneficial effect, with an RD of 0.08 (95% CI, 0.03–0.13; P = .004; I2 = 47%) and an NNT of 13 (95% CI, 8–33). This overall result was similar even

with the removal of the 2 trials of lower quality,18,21 with an RD of 0.07 (95% CI, 0.01–0.12; P = .02; I2 = 43%). Given that both analyses showed heterogeneity, however, we performed subgroup analyses on outcome timing and on dosage.

Outcome Timing

Combining the 3 studies reporting this outcome at 14 to 15 days14,17,20 showed no significant effect of intranasal corticosteroids, with an RD of 0.05 (95% CI, −0.01 to 0.11; P = .13; I2 = 22%) (Figure 2A). In contrast, combining the 3 studies that reported resolution or improvement at 21 days18,20,21 showed that intranasal corticosteroids had a significant beneficial effect with no heterogeneity, with an RD of 0.11 (95% CI, 0.06–0.17; P <.001; I2 = 0) and an NNT of 9 (95% CI, 6–17) (Figure 2B).

Figure 2Effect of intranasal steroids on resolution of symptoms of acute sinusitis at (A) 14 to 15 days and (B) 21 days.

In the 2 trials14,20 that reported the proportion of participants with persistent symptoms at 10 days after onset of treatment, there was no benefit of intranasal corticosteroids, with an RD of 0.06 (95% CI, −0.09 to 0.22; P = .41; I2 = 47%). Two trials reported a small but significant 7% absolute improvement in physician evaluation scores at 21 days in patients receiving intranasal steroids vs placebo (Nayak et al18: 61% vs 53%, P = .006; Meltzer et al21: 68% vs 61%, P <.01).

Dose-Dependent Benefit

Three trials using mometasone furoate nasal spray17,18,21 showed a significant effect on symptom resolution or improvement at 15 to 21 days, with an RD of 0.08 (95% CI, 0.01–0.14; P = .02; I2 = 62%) and an NNT of 13 (95% CI, 7–100). The daily dose of mometasone furoate ranged in these 3 trials from 200 μg to 800 μg. We therefore investigated the high heterogeneity by performing subgroup analysis by dose. As depicted in Figure 3, meta-regression analysis of mometasone furoate dose and symptom resolution showed a significant dose-response relationship (P = .02), with the effect size increasing with dose. For patients receiving 800 μg of mometasone furoate nasal spray daily, the RD was 0.12 (95% CI, 0.06–0.18; P = .0002) and the NNT was 8 (95% CI, 6–17); for those receiving 400 μg daily, the RD was 0.07 (95% CI, 0.03–0.11; P = .001) and the NNT was 14 (95% CI, 9–33).

Figure 3Dose-response relationship of mometasone furoate and likelihood of symptom resolution.

Individual Symptom Scores

Three RCTs reported individual symptom scores in 5 groups of patients who received different doses of mometasone furoate compared with placebo17,18,21 For each group, the symptoms of facial pain, nasal congestion, headache, rhinorrhea, postnasal drip, and cough were reported on a scale of 0 (none) to 3 (severe) at baseline and averaged across the first 15 days of therapy (see the Supplemental Appendix at http://www.annfammed.org/content/10/3/241/suppl/DC1 for full data). Compared with their counterparts who received placebo, patients who received intranasal corticosteroids in these 3 trials reported significantly greater improvement in facial pain (3 of the trials), congestion (3), rhinorrhea (2), headache (1), and postnasal drip (1) (all P <.05).

Adverse Events

One trial reported that no adverse events occurred with steroid therapy19; 2 trials reported no serious adverse events in either group14,20; and the remaining trials reported that adverse events were mainly mild or moderate in severity.17,18,21 Meta-analysis demonstrated no significant differences in the rate of overall adverse events between patients taking intranasal corticosteroids (299 of 1,299, or 23%) and placebo (181 of 797, also 23%) (P = .83). Common adverse events were headache (noted in 2%–8% of patients, 4 studies), epistaxis (3%–7%, 4 studies), nasal irritation (1%–2%, 3 studies), and pharyngitis (2%–4%, 3 studies). Meta-analysis of the rate of occurrence of these outcomes revealed no significant differences between steroid and placebo groups.

Relapse and Recurrence

Three trials17,19,20 reported the rate of relapse or recurrence of acute sinusitis up to 2 months after initiation of treatment. Recurrence occurred in 5% to 15% of patients taking intranasal corticosteroids and 4% to 37% taking placebo.

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DISCUSSION

Key Findings

This systematic review demonstrates that intranasal corticosteroids offer a small but significant symptomatic benefit in acute sinusitis. This effect is most marked when patients are given longer durations of treatment (21 days) and higher doses of the medication. Our analysis of individual symptom scores suggests that facial pain and nasal congestion may be most responsive to intranasal corticosteroids. In our main analysis, we found that whereas 66% of patients would experience improvement or resolution of symptoms at 14 to 21 days using placebo, an additional 7% of patients would achieve this outcome with corticosteroids, equating to an NNT of 13.

This 7% gain is a relatively small increase in the context of a self-limiting condition, and this clinical benefit must be set against potential harms and economic implications. Our included trials reported no serious adverse events associated with intranasal corticosteroid use and no increase in frequency of nonserious adverse events compared with placebo. Other potential

harms might include effects from systemic absorption; however, the single included trial addressing this outcome found no clinically relevant changes in the hypothalamic-pituitary-adrenal axis,20 and 2 recent reviews found no evidence of suppression of this axis or of growth suppression with intranasal corticosteroids.22,23

Only 1 included trial assessed the potential benefit of intranasal corticosteroids for work and quality of life outcomes in acute sinusitis.20 In this trial, the corticosteroid group had a significantly higher subjective level of work performance (median, 100% vs 90% for placebo); however, there were no differences in work attendance or changes in quality of life as measured by the 20-item Sino-Nasal Outcome Test (SNOT-20)24 and the 12-Item Short Form Health Survey.25 An individual patient with acute sinusitis may therefore experience negligible adverse effects of intranasal corticosteroids in return for a small increase in likelihood of earlier resolution. This may be an acceptable trade-off for some patients. The therapeutic benefit at the population level is currently unclear.

Our subgroup analysis suggests the benefit of intranasal corticosteroids is most marked at 21 days, with an additional 11 patients experiencing symptom resolution for every 100 treated. In contrast, this effect was not significant at 15 days. Our subgroup analysis had only a small number of trials, however, and further research is needed to clarify the clinical benefit at 15 days or less (as discussed below). Clearly, patients are likely to experience pronounced symptoms in the first 7 to 14 days of their illness and may be less willing to consider a therapy that does not offer an increased likelihood of improvement in this earlier time period.

We found evidence of a dose-response relationship for mometasone furoate nasal spray: larger doses were associated with a greater likelihood of symptom resolution. We had insufficient data to assess whether other types of intranasal corticosteroids showed a similar effect, or whether this higher dose was associated with an increase in adverse events. On the basis of our review, when intranasal corticosteroids are used, we recommend doses of 800 μg of mometasone furoate daily.

Comparison With Existing Literature

The small benefit of intranasal corticosteroids for the broad measure of symptom resolution or improvement at 14 to 21 days was similar in direction and size to that found in a recent Cochrane review.13 In both cases, however, marked heterogeneity was present. We have demonstrated that this heterogeneity arises from both the variation in the timing of the outcome measure and the dose of intranasal corticosteroids used. We found larger effect sizes in subgroup analyses by dose and timing of outcome measure. The recent Cochrane review may therefore have underestimated the benefit of intranasal corticosteroids. Williamson et al14 acknowledged that their RCT was underpowered to detect clinically useful effects, and the study may have used an inappropriately low dose of budesonide.26

Limitations

Important limitations of this systematic review include first, that 5 of the studies prescribed antibiotics to both steroid and placebo groups. Williamson et al14 found no interaction between

antibiotic therapy and steroid therapy using a factorial design, which argues against a synergistic effect of these drug classes.

Second, included studies varied in the types and doses of steroids, duration of therapy, and outcome measures reported. Particularly, the definition of resolution of symptoms varied among the studies, and all measures of resolution involved subjective assessment. These factors prevented pooling of all outcomes and are likely to have contributed to the heterogeneity of the data.

Third, included studies were underpowered to detect rare adverse effects of corticosteroid, as well as relapse rates and days missed from work or school. Fourth, the limited number of trials meant we were unable to assess publication bias using funnel plots or place undue weight on the findings from small subgroup analyses. Finally, in 4 of the 6 included trials, radiologic or endoscopic evidence of acute sinusitis was an inclusion criterion. In ambulatory care, it is impractical and inappropriate to perform radiologic investigations on patients with symptoms of sinusitis.

Recommendations for Research

This review highlights the need for adequately powered RCTs comparing intranasal corticosteroids with placebo in the absence of antibiotics for symptom relief in acute sinusitis. We recommend that trials should use at least 21 days of therapy with high-dose mometasone furoate nasal spray. Inclusion criteria should be based on a clinical scoring system rather than radiologic evidence. Self-report and telephone follow-up should be used to assess the time to complete resolution of symptoms and also the time to onset of symptom resolution, which will be particularly important in clarifying whether there is benefit at time points earlier than 21 days. Recording the duration of symptoms at baseline will also improve our understanding of patterns of symptom resolution.

As acute sinusitis is diagnosed in an estimated 31 million Americans annually,1 a full assessment of economic implications is important. Such assessment should look at the cost of 21 days of therapy with high-dose mometasone furoate (equivalent to 3 bottles containing 140 × 50-μg doses) and the indirect cost savings in terms of attendance and performance at work or school and quality of life measures (eg, with the SNOT-20 score).24 These data will improve our understanding of whether the small benefit of this therapy for the individual has larger benefits at the population level. Antibiotics are widely prescribed for acute sinusitis despite limited evidence of beneficial effect; thus, measuring the extent to which intranasal corticosteroids reduce antibiotic prescribing will be highly relevant to clinical practice and policy. A systematic review using individual patient data may improve our ability to combine the data from existing research. Finally, a double-blind, placebo-controlled trial of the benefit of oral steroids in acute sinusitis has not yet been performed. Since delivery of intranasal corticosteroids to the nasal mucosa may be reduced by nasal congestion, and this may be a factor responsible for our finding of a nonsignificant benefit at 15 days, oral drug delivery might offer earlier and greater symptomatic relief.

In summary, on the basis of the current evidence, we believe that intranasal corticosteroids offer a small therapeutic benefit in acute sinusitis and may be most helpful for symptoms of facial pain and nasal congestion. This benefit may be greater with courses of 21 days in duration and with high-dose mometasone furoate. Future trials in antibiotic-naïve patients that clarify the time-course of clinical benefit and the impact on work and quality of life will be important to guide management of this common condition in family practice.

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AcknowledgmentsWe would like to acknowledge the input of Professors Paul Glasziou and Chris Del Mar into the initial stages of this project.

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FootnotesConflicts of interest: authors report none.

Disclaimer: Neither the British Society for Antimicrobial Chemotherapy nor the National Institute of Health Research had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Funding support: Funding for this work was provided in part by a grant from the British Society for Antimicrobial Chemotherapy Systematic Review Grant (GA722SRG). The Department of Primary Health care is part of the National Institute of Health Research (NIHR) School of Primary Care Research.

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5. Rosenfeld RM, Singer M, Jones S. Systematic review of antimicrobial therapy in patients with acute rhinosinusitis. Otolaryngol Head Neck Surg. 2007;137(3 Suppl):S32–S45. [PubMed]6. Young J, De Sutter A, Merenstein D, et al. Antibiotics for adults with clinically diagnosed acute rhinosinusitis: a meta-analysis of individual patient data. Lancet. 2008;371(9616):908–914. [PubMed]7. Ah-See KW, Evans AS. Sinusitis and its management. BMJ. 2007;334 (7589):358–361. [PMC free article] [PubMed]8. Shaikh N, Wald ER, Pi M. Decongestants, antihistamines and nasal irrigation for acute sinusitis in children. Cochrane Database Syst Rev. 2010;(12):CD007909. [PubMed]9. Low DE, Desrosiers M, McSherry J, et al. A practical guide for the diagnosis and treatment of acute sinusitis. CMAJ. 1997;156(Suppl 6): S1–S14. [PubMed]10. Candy B, Hotopf M. Steroids for symptom control in infectious mononucleosis. Cochrane Database Syst Rev. 2006;3:CD004402. [PubMed]11. Russell K, Wiebe N, Saenz A, et al. Glucocorticoids for croup. Cochrane Database Syst Rev. 2004;(1):CD001955. [PubMed]12. Hayward G, Thompson M, Heneghan C, Perera R, Del Mar CB, Glasziou P. Corticosteroids for pain relief in sore throat: systematic review and meta-analysis. BMJ. 2009;339:b2976. [PMC free article] [PubMed]13. Zalmanovici A, Yaphe J. Intranasal steroids for acute sinusitis. Cochrane Database Syst Rev. 2009;(4):CD005149. [PubMed]14. Williamson IG, Rumsby K, Benge S, et al. Antibiotics and topical nasal steroid for treatment of acute maxillary sinusitis: a randomized controlled trial [see comment]. JAMA. 2007;298(21)2487–2496. [PubMed]15. Dickersin K, Manheimer E, Wieland S, Robinson KA, Lefebvre C, McDonald S. Development of the Cochrane Collaboration’s CENTRAL Register of controlled clinical trials. Eval Health Prof. 2002;25(1):38–64. [PubMed]16. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560. [PMC free article] [PubMed]17. Meltzer EO, Bachert C, Staudinger H. Treating acute rhinosinusitis: comparing efficacy and safety of mometasone furoate nasal spray, amoxicillin, and placebo. J Allergy Clin Immunol. 2005;116(6): 1289–1295. [PubMed]18. Nayak AS, Settipane GA, Pedinoff A, et al. ; Nasonex Sinusitis Group Effective dose range of mometasone furoate nasal spray in the treatment of acute rhinosinusitis. Ann Allergy Asthma Immunol. 2002;89(3):271–278. [PubMed]19. Barlan IB, Erkan E, Bakir M, Berrak S, Başaran MM. Intranasal budesonide spray as an adjunct to oral antibiotic therapy for acute sinusitis in children. Ann Allergy Asthma Immunol. 1997;78(6):598–601. [PubMed]20. Dolor RJ, Witsell DL, Hellkamp AS, Williams JW, Jr, Califf RM, Simel DL.; Ceftin and Flonase for Sinusitis (CAFFS) Investigators Comparison of cefuroxime with or without intranasal fluticasone for the treatment of rhinosinusitis. The CAFFS Trial: a randomized controlled trial [see comment]. [Erratum appears in JAMA. 2004;292(14):1686]. JAMA. 2001;286(24):3097–3105. [PubMed]21. Meltzer EO, Charous BL, Busse WW, Zinreich SJ, Lorber RR, Danzig MR.; The Nasonex Sinusitis Group Added relief in the treatment of acute recurrent sinusitis with adjunctive mometasone furoate nasal spray [see comment]. J Allergy Clin Immunol. 2000;106(4):630–637. [PubMed]

22. Demoly P. Safety of intranasal corticosteroids in acute rhinosinusitis. Am J Otolaryngol. 2008;29(6):403–413. [PubMed]23. Derendorf H, Meltzer EO. Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications. Allergy. 2008;63(10):1292–1300. [PubMed]24. Piccirillo JF, Merritt MG, Jr, Richards ML. Psychometric and clinimetric validity of the 20-Item Sino-Nasal Outcome Test (SNOT-20). Otolaryngol Head Neck Surg. 2002;126(1):41–47. [PubMed]25. Ware JE, Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996;34(3):220–233. [PubMed]26. Meltzer EO. Antibiotics and nasal steroids for acute sinusitis. JAMA. 2008;299(12):1422–1423, author reply 1423. [PubMed]

Management of Rhinitis: Allergic and Non-AllergicNguyen P Tran,1 John Vickery,1 and Michael S Blaiss 1,2

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AbstractRhinitis is a global problem and is defined as the presence of at least one of the following: congestion, rhinorrhea, sneezing, nasal itching, and nasal obstruction. The two major classifications are allergic and nonallergic rhinitis (NAR). Allergic rhinitis occurs when an allergen is the trigger for the nasal symptoms. NAR is when obstruction and rhinorrhea occurs in relation to nonallergic, noninfectious triggers such as change in the weather, exposure to caustic odors or cigarette smoke, barometric pressure differences, etc. There is a lack of concomitant allergic disease, determined by negative skin prick test for relevant allergens and/or negative allergen-specific antibody tests. Both are highly prevalent diseases that have a significant economic burden on society and negative impact on patient quality of life. Treatment of allergic rhinitis includes allergen avoidance, antihistamines (oral and intranasal), intranasal corticosteroids, intranasal cromones, leukotriene receptor antagonists, and immunotherapy. Occasional systemic corticosteroids and decongestants (oral and topical) are also used. NAR has 8 major subtypes which includes nonallergic rhinopathy (previously known as vasomotor rhinitis), nonallergic rhinitis with eosinophilia, atrophic rhinitis, senile rhinitis, gustatory rhinitis, drug-induced rhinitis, hormonal-induced rhinitis, and cerebral spinal fluid leak. The mainstay of treatment for NAR are intranasal corticosteroids. Topical antihistamines have also been found to be efficacious. Topical anticholinergics such as ipratropium bromide (0.03%) nasal spray are effective in treating rhinorrhea symptoms. Adjunct therapy includes decongestants and nasal saline. Investigational therapies in the treatment of NAR discussed include capsaicin, silver nitrate, and acupuncture.

Keywords: Allergic rhinitis, nonallergic rhinitis, intranasal corticosteroids, immunotherapy, intranasal antihistamines, oral antihistamines

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ALLERGIC RHINITIS

Definition

Rhinitis is defined as the presence of at least one of the following: congestion, rhinorrhea, sneezing, nasal itching, and nasal obstruction.1,2 Other reported symptoms include throat clearing, headaches, facial pain, ear pain, itchy throat and palate, snoring, and sleep disturbances.3,4 A system of rating symptom severity has been developed using a 7-point visual analog scale that includes elements of nasal symptoms, non-nasal symptoms, and the effects of medications. (See reference for copies of assessment forms).5 Allergic rhinitis is present when these symptoms are triggered by an allergen. Perennial allergic rhinitis is most often attributed to dust mites, mold spores, and animal dander, whereas seasonal allergic rhinitis is attributed to a large variety of pollens that varies based on geographical region.2

Epidemiology

Allergic rhinitis is very common condition throughout the world.6 In the United States it affects between 10-30% of the adult general population and up to 40% of children. This accounts for 30-60 million people in the United States1 and the prevalence has been increasing in recent decades,2

making it the fifth most common chronic disease in the US.7 Risk factors include an atopic family history, IgE levels above 100 IU/mL before the age of 6 years, higher socioeconomic status, and positive epicutaneous allergen testing.1 However, 44-87% of people with rhinitis have mixed allergic and non-allergic rhinitis,1 and therefore all that sneezes is not necessarily purely allergic in etiology.

While many patients downplay rhinitis symptoms as an inconvenience rather than a disease, the economic burden is quite significant. In the United States, the direct medical costs (physician services, diagnostics, medications, etc.) nearly doubled from US$6.1 billion in 2000 to US$11.2 billion in 2005.8 In Europe, it was estimated that by the late 1990s, €1.0-1.5 billion were spent on direct costs.2 Additionally, the indirect costs (travel for physician visits, decreased work productivity, missed school and loss of parents' pay from missed work to care for their children, etc.) are also considerable. In the US, there are 3.5 million lost workdays and 2 million lost school days due to allergic rhinitis. It is estimated that productivity decreases by US$600 per affected employee per year, which is a greater loss than asthma, diabetes, and coronary heart disease. Overall, allergic rhinitis was the fifth costliest chronic disease in the United States with 75% of the costs coming from decreased productivity.4,8 The indirect costs in Europe were estimated to be more than the direct costs at €1.5-2.0 billion.2

Pathophysiology

Cellular signals

Allergic rhinitis is an IgE-mediated disease resulting in inflammation of the nasal mucosa. Allergic patients have increased levels of allergen specific IgE in their nasal mucosa compared to controls. Histamine release from resident mast cells is a major mediator in the inflammation of allergic rhinitis. Eosinophilic inflammation also plays an important role. A Th2 response ensues with the release of IL-4 and IL-5. Recently, thymic stromal lymphopoietin (TSLP), IL-25 (or IL-17E), and IL-33 have also been implicated. As eosinophils produce IL-5 and granulocyte macrophage-colony stimulating factor (GM-CSF), they perpetuate their own survival. After allergen exposure, rhinitis can persist for several weeks.2,9 There is an immediate and a late phase to allergic rhinitis. Both are characterized by the same symptoms, but the late phase's predominate symptom is nasal congestion. Eosinophils release mediators that can induce tissue damage, and pre-treating with topical glucocorticoids reduces eosinophil infiltration and cytokine release.1

Neuronal aspects

The interplay between sensory nerve fibers and the efferent sympathetic and parasympathetic neurons helps to regulate the mucosal barrier of the nasal epithelium. The thinly myelinated Aδ fibers convey the sensations of pain and cold to the central nervous system. A thick mucosal lining decreases the ability of these neurons to sense passing airflow, which contributes, to the sensation of nasal obstruction and dyspnea. When menthol receptors on these nerves are

stimulated, the result is a false sense of nasal patency and less dyspnea. After the initial rapid stimulation of Aδ fibers, a delayed activation of the non-myelinated slowly conducting C fibers ensues. In addition to multiple allergens, the C fibers can be stimulated by nicotine, cigarette smoke, aldehyde, formaldehyde, isocyanates, sulfur dioxide, and other toxicants. Capsaicin is the naturally occurring substance in spicy peppers that induces the sensation of heat, and it activates transient receptor potential and ion channel proteins (TRPs). A stinging sensation similar to that induced by capsaicin occurs when the osmotic tonicity rapidly changes at the cellular surface. This can happen when dry pollen and dust grains land on mucosal surfaces, causing water to efflux from epithelial cells.

Acetylcholine is released from parasympathetic nerve fibers that innervate glands and vessels of the airway mucosa. Eosinophils interfere with the activation of the presynaptic M2 muscarinic receptor, which decreases the negative feedback on acetylcholine release. The result is an increase in bronchoconstriction and glandular secretion. To balance the effects of the parasympathetic nervous system, sympathetic neurons induce vasoconstriction in the epithelium. Stimulation of α-adrenergic receptors by nasal decongestants (discussed below) reduces mucosal thickness.

The nociceptive C fibers innervate glands and deep subepithelial vessels. Their release of substance P may lead to increased expression of E-selectin and VCAM on endothelial cells. The result is increased infiltration of leukocytes, which is a critical part of the late-phase response of allergic rhinitis. Interestingly, when substance P is administered to allergic individuals, mRNA levels of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, TNFα, and γ-interferon vs. only an increase of IL-6 and IL-6 mRNA in non-allergic individuals. Neural plasticity also comes into play in allergic subjects. This occurs when persistent stimulation from allergens increases the sensitivity of involved neurons to depolarize. Allergic individuals' neurons will depolarize in the presence of bradykinin and endothelin, whereas these substance induce no response in non-allergic subjects.

Because it is more difficult to localize visceral compared to peripheral sensations, the activation of nerve fibers that innervate deep tissues often results in referred pain. Sinus headaches are a common example. Noxious stimulation of the inferior turbinate induces the sensation of pain in the maxillary teeth, zygoma, and eyes. The middle turbinates refer pain to the temple, zygoma, inner canthus, and forehead.10

Genetics

Monozygotic twins show a concordance of 45-60% in the development of allergic rhinitis, and dizygotic twins have a concordance rate of about 25%. These data point to a genetic link. However studies into the genetics of allergic rhinitis are lacking, and current findings are preliminary. Chromosome 3 has three regions linked to allergic rhinitis, 3q13, 3q13.31, and 3p24. A possible involved region on chromosome 4 is 4q24-q27. Certain single nucleotide polymorphisms (SNPs) have been implicated GATA3 and IL-13.9 Specific HLA haplotypes have been associated with allergic responses to particular allergens. This may be due to more than just an association since HLAs present antigens to T-cells. There is also evidence that points to genetic associations of the T-cell receptor (TCR) α-chain and the high affinity IgE receptor

FcεRI with increased allergy. Other candidate genes for further investigation include those involved with the production of IgE, IL-4, IL-5, and IL-13.11

Treatment

Avoidance

Since allergic rhinitis is induced by specific allergens, it makes sense that avoiding those triggers would be an effective treatment. However, this is not always possible as in the case of pollens, and for those with mixed allergic and non-allergic rhinitis, avoidance will not completely alleviate their symptoms. Some allergens can and should be avoided as the severity of rhinitis correlates with the levels of allergens in the environment. Precautions can be taken against dust mites. Carpet removal, removal of soft toys from the bedroom, using allergen-impermeable bedding covers for the mattress and pillow, vacuuming with a high-efficiency particulate air (HEPA) filter, and washing bedclothes and bed sheets in hot water (60℃) are helpful. Any single method alone is unlikely to provide benefit, and patient should be encouraged to use multiple interventions. For those with animal allergies, ideally, removal of the pet from the home would be best along with careful vacuuming of all carpets, upholstered furniture, and mattresses. It may be impossible to clear cat dander or take up to 20 weeks for cat dander levels to decrease to cat free homes. Isolating the pet to a single room and using a HEPA filter is a second best option. Studies have been inconsistent on the benefits of regular bathing of cats.1,2 Spaying or neutering cats and dogs increases levels of their major allergens found in homes, Fel d 1 and Can f 1 respectively. Having fewer pets correlates with lower dander levels. Interestingly, keeping cats outside does not significantly reduce the presence of Fel d 1, while the less access dogs have to the home and bedroom correlates with lower amounts of Can f 1 found in the bedroom.12,13 Environmental moisture control can improve mold levels. Using pesticides and meticulous control of food debris can decrease cockroach environmental allergens. However, it may take over 6 months to remove residual cockroach allergen.1

Antihistamines

Histamine activates the H1 receptor on a distinct set of neurons to produce the sensation of itching. This leads to sneezing, nose rubbing, and the "allergic salute."10 H1-antihistamines are inverse agonists, rather than H1-antagonists, that combine with and stabilize the inactive form of the H1 receptor leading toward a shift in equilibrium to the inactive state. In addition to the inverse agonist effect at the H1 receptor, the newer second-generation agents have both anti-allergic and anti-inflammatory properties.

The first generation H1 antihistamines such as diphenhydramine, chlorpheniramine, brompheniramine and hydroxyzine are also referred to as the sedating antihistamines. These agents are effective at controlling the rhinorrhea, sneezing and pruritus associated with allergic rhinitis. Unfortunately these agents cross the blood-brain barrier thus producing undesirable side effects such as central nervous system depression, sedation leading to impaired performance at home, work and school and cardiotoxicity. There are no long-term safety studies on the first generation antihistamines. These agents have poor H1 receptor selectivity and act on muscarinic receptors causing anticholinergic effects such as dry mouth, urinary retention, constipation and

tachycardia. The second-generation antihistamines developed in the early 1980's, have improved H1 receptor selectivity, absent or decreased sedation, faster onset and longer duration of action and fewer adverse effects. Their half-lives are longer (12-24 hours) compared to the first generation (4-12 hours).14 Of the second generation H1-antagonists, fexofenadine has no sedating effects even at higher than recommended doses. Loratadine and desloratadine are non-sedating at recommended doses but may cause sedation at higher doses. Cetirizine, and its purified enantiomer levocetirizine, have more sedation potential that other second generation H1-antagonists.15 All rhinitis symptoms, except for obstruction, can be alleviated by H1-antihistamines, and there does not seem to be a superiority of any one of the second generation H1-antihistmines over another.

Topical H1-antihistamines (azelastine, olopatadine) provided faster onset of action (less than 15 minutes) and similar to greater efficacy compared to oral preparations in regard to rhinitis and conjunctivitis. There has even been an association with improvement of congestion. However, their results are limited to the local organ effects, and require twice daily use to maintain a sustained response; whereas second generation oral H1-antagonists can be taken on a daily basis. Some patients may complain of a bitter taste, and intranasal H1-antagonists are less effective than intranasal steroids.1,2 In a direct comparison trial between azelastine nasal spray versus oral cetirizine, azelastine was found to have a significant improvement in nasal symptom scores for the specific symptoms of sneezing and nasal congestion over cetirizine.16

Steroids

In addition to oral H1-antihistamines, intranasal corticosteroids are a mainstay of treatment. They are the most effective medications for controlling all rhinitis symptoms. Their onset of action is from 3-12 hours. Their use on an as needed basis is not as effective as continual use1 but may not be required continually in all patients. They are generally safe, and there is little evidence to support suppression of the hypothalamic-pituitary-adrenal axis with prolonged use. Side effects are generally mild (crusting, dryness, and minor epistaxis). They can be minimized by proper nasal spray technique. Septal perforation has only been described anecdotally.2 For patients whose symptoms are not optimally controlled with intranasal steroids, adding an intranasal (but not oral) antihistamine may give some additional benefit.3

Systemic corticosteroids should be considered a last resort treatment option, but they may be necessary for severe or intractable symptoms. If they are used, then oral is preferred over parenteral because of the lower risk of systemic side effects and the ability to adjust doing. Steroids should never be injected into the turbinates. Recommendations on short courses oral steroids differ from 5-7 days1 to no more than 3 weeks.2

Decongestants

Decongestants are also available in oral and topical formulations. They are effective in relieving congestion. However, studies of H1-antihistamine in combination with oral decongestants failed to show improved benefit compared to either alone. Side effects include insomnia, anorexia, irritability, and rarely elevated blood pressure. Oral decongestants should be avoided in children less the 1-year of age, adults over 60 years of age, and any patient with a cardiac condition. The

main side effect of topical decongestants is the development of rhinitis medicamentosa, which can appear in some patients after only 3 days of use or not at all in other patients after six weeks of use. European guidelines recommend a maximum of 10 days use.1,2

Cromones

Intranasal formulations of cromolyn and nedocromil have been used to treat allergic rhinitis but are less effective than topical corticosteroids. It is believed that cromones are less effective than topical antihistamines2, but adequate comparative studies have not been performed.1 Although the exact mechanism is unknown, they work mainly by inhibiting mast cell activation. Studies have shown that nedocromil inhibits the activation of neutrophils, eosinophils, monocytes, and macrophages as well. There may even be an inhibitory effect on neural signals involved in rhinitis.2 Overall, they are safe with minimal to no side effects.1,2

Miscellaneous

The anticholinergic ipratropium bromide is available in a nasal form and blocks the parasympathetic signaling that leads to watery rhinorrhea, and it has been shown effective in controlling this particular symptom. There are little to no side effects. Guidelines state it does not decrease sneezing or nasal obstruction,1,2 but one study in children showed improvement in rhinorrhea, congestion, and sneezing although to a lesser degree than intranasal steroids.17

Leukotriene receptor antagonists have been shown to be effective controlling allergic rhinitis, and they are comparably effective with oral antihistamines.1 After 2 weeks of therapy, montelukast progressively decreased symptoms scores, but still to a lesser degree than intranasal fluticasone.18 For patients whose symptoms are not controlled with intranasal corticosteroids, adding montelukast did not offer any further benefit.19

The anti-IgE antibody omalizumab may be efficacious, but it has not been shown to be superior to current allergic rhinitis treatments. Additionally, its high cost limits it use as a standard treatment.1

Taken as a whole, intranasal corticosteroids seem to be the most effective in controlling nasal symptoms. The next most effective are oral and intranasal antihistamines. However, it is difficult to fully stratify medication classes because of the lack of sufficient uniform data. For instance, studies on antihistamines have excluded nasal congestion as a component of symptoms scores because they are not expected to improve this symptom. There may be some differences between seasonal and perennial allergic rhinitis where, for some patients with perennial allergic rhinitis, oral antihistamines may be as effective as nasal steroids. Additionally, there is variable response to treatments among individuals.3 Table 1 lists the effectiveness of different medications in symptom control of allergic rhinitis.

Table 1

Effectiveness in symptom control of various medications for allergic rhinitis

Immunotherapy

Subcutaneous immunotherapy (SCIT) has been shown to be effective in treating allergic rhinitis in patients with identifiable IgE mediated symptom triggers. It has some advantages over the above mention treatments. Effects can be sustained for years, and it may prevent the development of new allergen sensitivities or even asthma.1 It is effective for not only control of allergic rhinitis but also of allergic conjunctivitis and allergen induced asthma.20 However, immunotherapy is underutilized with only 2 to 3 million US individuals on SCIT of the estimated 55 million people with allergic diseases.21 In regard to specific inhaled allergens, evidence supports immunotherapy for pollens, animal dander, and dust mite. Large local reactions at the injection site are the most common adverse reaction. The risk of severe systemic reactions during subcutaneous immunotherapy is rare but present in less than 1% of those receiving standard immunotherapy. Near fatal events occurred at a rate of 5.4 per million injections. High ambient pollen levels and dosing errors were the two main risk factors for such a reaction. It is advised that patients receive immunotherapy injections in a setting with staff and equipment that can handle anaphylaxis, and that patient be observed for 30 minutes after each injection.20 Other disadvantages include injection discomfort, the frequency of shot visits, and the total cost. However, immunotherapy is the only treatment that can modify the disease. When the direct costs of symptomatically managed allergic rhinitis are compared to the cost of immunotherapy, the values are virtually the same.8 When indirect costs are factored, immunotherapy may be much more economical.

Subcutaneously is the most common way to deliver immunotherapy, but sublingual immunotherapy (SLIT) is also used. SLIT has been reported to cause oral itching and gastrointestinal side effects, but in most studies, these rates seem to be the same as those observed in the placebo arm.2 There is a lack of standardization in SLIT with timothy grass pollen extracts being the only commercially available therapy (Grazax by ALK-Abelló Hørsholm. Denmark), and there are no SLIT therapies approved for the US by Food and Drug Administration. Advantages of SLIT include an extremely low risk of anaphylaxis and the ability to begin therapy at the maintenance dose without a build-up phase.22 SLIT for dust mite allergy has been specifically studied in the Korean population and found to be effective in reducing symptom scores.23,24 Although anaphylaxis has not been noticed in studies on SLIT, there are case reports of anaphylaxis occurring during treatment, even with the first dose.21 SLIT is not as well established as SCIT, and further investigation is required to determine the optimal dose and patient selection.2

A meta-analysis25 done in January of 2010 reviewed the past 20 years of studies on SLIT. Nineteen studies were included with a total of 2,971 study subjects. SLIT was found to improve both symptom scores and medication use for allergic rhinitis. It appears that a minimal dose of 450 µg of antigen per treatment was necessary and that using higher doses produced to benefit. Upon subgroup analysis, SLIT was far less effective in children than adults. This conclusion may have been confounded by the fact that most of the pediatric studies used doses of less than 276 µg and the only pediatric study that showed statistically significant benefit used a dose of 600

µg. Along these lines, the meta-analysis showed that SLIT tablets were more effective than drops in reducing symptom scores with the caveat that this difference is mostly noticed in pediatric studies where drops administered a lower dose than tablets. Additionally, some of the pediatric studies included allergens other than grass. Other pertinent conclusions were: that SLIT was more effective when given for 12 months or less compared to over 1 year of use; SLIT was not more effective for rhinitis control in allergic asthmatics than in subjects without allergic asthma; and the more important that the length of treatment was the timing of beginning SLIT with initiation at least three months before grass season being optimal.

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NONALLERGIC RHINITIS

Definition

Nonallergic rhinitis (NAR) is generally described as chronic nasal symptoms, such as obstruction and rhinorrhea that occur in relation to nonallergic, noninfectious triggers such as change in the weather, exposure to caustic odors or cigarette smoke, barometric pressure differences, etc. There is a lack of concomitant allergic disease, determined by negative skin prick test for relevant allergens and/or negative allergen-specific antibody tests.26 The term vasomotor is often used which suggests involvement of neural, glandular, and vascular pathways; however, this term is misleading because it implies a true understanding of the underlying pathophysiology of the disease when this has not been definitively established.27

In December of 2008, a roundtable conference which included 8 expert physicians on rhinitis convened to establish a consensus on the clinical definition of nonallergic vasomotor rhinitis and to develop appropriate inclusion and exclusion criteria for the enrollment of subjects in future clinical studies. From this NAR Consensus Panel Proceedings, there were at least 8 subtypes that filled the criteria for NAR (Table 2).1,26,28 Nonallergic rhinopathy (formerly known as vasomotor rhinitis) accounts for the majority of NAR. It is a diverse group of patients that have chronic nasal symptoms with a lack of nasal eosinophilia and an etiology that is neither immunologic nor due to infection. NAR with eosinophilia is characterized by patients who have year-round nasal symptoms but eosinophils are found on nasal smear though they lack positive skin tests and/or specific IgE antibodies in the serum. Atrophic rhinitis, as the name implies, refers to a chronic condition in which there is progressive atrophy of the nasal mucosa with crusting and dryness as the most prominent features. It is typically not inflammatory mediated.1 Senile rhinitis occurs most commonly in the elderly, presents mostly with watery rhinorrhea that may worsen after certain foods or environmental irritants. Gustatory rhinitis occurs after eating, especially hot or spicy foods. Rhinitis medicamentosa is included in drug-induced rhinitis, though a variety of medications have been implicated in causing chronic nasal congestion. Rhinitis medicamentosa most commonly occurs after repeated use of topical nasal decongestants such as oxymetzaoline or phenylephrine. Hormone induced rhinitis refers to the congestion and nasal symptoms that occur in response to endogenous female hormones, such as seen in pregnancy. Cerebrospinal fluid (CSF) leak should be considered in patients with a history of cranio-facial trauma or past facial surgery that have persistent, clear rhinorrhea.26

Table 2

Chronic rhinitis subtypes not associated with allergies, infection, or anatomic abnormalities

Epidemiology

The exact prevalence and impact of NAR is not as established as it is for allergic rhinitis. It is estimated that it affects more than 19 to 20 million patients in the United States, with vasomotor rhinitis being the most common subtype seen.26,29 European studies evaluating the prevalence of NAR found that approximately 1 in 4 patients with nasal symptom complaints had "pure" NAR and it is estimated that 50 million Europeans have NAR, with a total prevalence of more than 200 million worldwide.26

With many subtypes of disease, the true economic burden of NAR is most likely grossly underestimated. Schatz et al.29 reviewed the records of more than 1 million patients enrolled in the Kaiser Permanente Southern California Medical care program from 2002-2005 and found that 15% had at least 1 encounter with the diagnosis. Another 14% received rhinitis medication with no medical encounter. They also found that patients from either group had significantly more health care visits per year for asthma (2-4 times as many), acute sinusitis (6-8 times as many) and all other diagnoses (almost twice as many). They also found that patients with rhinitis or treated for rhinitis had a higher prevalence of comorbid diseases such as asthma, acute and chronic sinusitis, nasal polyposis, conjunctivitis, acute otitis media, chronic serous otitis media, sleep apnea, and fatigue. When reviewing the patient demographics, those with NAR were significantly older, mean age of 42.6 vs. 35.8 and more likely to be female than the patients with the diagnosis of allergic rhinitis.29

Importance of treatment

As Ledford30 points out in his symposium on assessing the damage of inadequately diagnosed NAR, patients are often empirically treated with oral second generation antihistamines, which are usually not sufficient in relieving their symptoms. The patients are then subjected to multiple rounds of treatment failures that lead to frustration towards seeking medical care and medication use. They must incur additional expenditures for doctor appointments, medication prescriptions, and lost time from work on top of their reduced quality of life. Besides this decrease in quality of life, untreated rhinitis does significantly increase the risk of other comorbid conditions such as obstructive sleep apnea, fatigue, headache, malaise, poor appetite and weakness. This effect is not limited to impaired work performance in adults but can also manifest as learning disabilities, behavioral, and psychological effects in children. Children are also at risk for permanent facial

changes from untreated rhinitis such as increased facial length, retrognathic maxilla and mandible, and dental malocclusions from obstructed breathing.30

Beyond these physical and emotional impacts on patients there is also an economic burden from the incomplete diagnosis and treatment of rhinitis. Recent evidence shows that asthma and rhinitis are often coexisting in atopic and nonatopic patients and that effective treatment of rhinitis frequently improves asthma.31

Treatment

Avoidance

Avoidance of environmental triggers such as strong odors (perfumes, soaps, paint, etc.) and air pollutants (smoke fumes, tobacco smoke) that are respiratory irritants is recommended in those who find these worsen their rhinitis symptoms.1,32

Antihistamines

Oral second generation antihistamines are not as effective in the treatment of NAR, though first generation oral antihistamines may haves some benefit due to anticholinergic activity.33 Topical antihistamines on the other hand have been found to be very effective for the overall treatment of NAR. Of the two topical antihistamines on the market in the United States (azelastine and olopatadine), azelastine is the only one that has been shown to be efficacious for nonallergic rhinitis.1,32,34 Banov and Lieberman32 evaluated the efficacy of the azelastine nasal spray in patients with nonallergic vasomotor rhinitis in a multicenter, randomized, placebo-controlled trial and found a significant improvement in total vasomotor rhinitis symptom scores (TVRSS) in those patients receiving azelastine (two sprays twice a day, 1.1 mg) versus placebo. In an open label, 2-week study with azelastine 2 sprays per nostril twice daily in patients with allergic rhinitis, mixed rhinitis, and nonallergic vasomotor rhinitis it was found that azelastine had improvement in control of all rhinitis symptoms including nasal congestion, postnasal drip, sneezing, and sleeping difficulty.34 The previously mentioned metallic aftertaste that some patients describe with azelastine is dose-dependent and often dissipates over time.33

Steroids

Intranasal corticosteroids have been found to be effective in nonallergic rhinitis, especially in vasomotor rhinitis and NARES. Fluticasone propionate and beclomethasone are the only topical corticosteroids approved by the FDA in the US for the treatment of NAR. Clinically, there does not appear to be a difference between the intranasal steroids available at this time.1 Most are dosed twice daily and patients should be informed that it may take 24 to 72 hours before symptoms start to improve though the onset of action is said to be from 3-12 hours.33 In a randomized, double-blind, placebo-controlled trial with 983 patients with perennial nonallergic rhinitis performed by Webb et al.35 patients received fluticasone propionate 200 mcg, 400 mcg or placebo for 28 days. Primary endpoint was the mean change in total nasal symptom score (TNSS), which was a sum of patient ratings of nasal obstruction, postnasal drip, and rhinorrhea. Patients that were found to have NARES as well as those that did not, were shown to have

similar statistically significant improvement on either dose of fluticasone propionate compared with placebo.33 However, there is a subgroup of NAR patients that fail to respond to intranasal corticosteroids and further study is warranted in these nonresponders.36

Decongestants

Currently there are no specific studies looking at the effectiveness of oral decongestants in the treatment of NAR. Thus, they should be considered adjunctive therapy, which is used on an as needed basis for nasal congestion that is not responsive to intranasal corticosteroids, topical antihistamines, or a combination of both.

Anticholinergics

The only topical anticholinergic medication approved in the United States for topical application is ipratropium bromide. Ipratropium bromide (0.03%) nasal spray is recommended when rhinorrhea is the predominant or only symptom, as in the case of gustatory rhinitis. From the updated rhinitis practice parameters, its use in combination with an intranasal corticosteroid is more effective than either drug alone for the treatment of rhinorrhea. This is not only effective, but safe as well since there is not an increased incidence of adverse events.1

Nasal saline

Nasal lavage with saline solution has also been found to be a helpful alone or as an adjuvant therapy in patients with chronic rhinorrhea and rhinosinusitis.1 It is best performed immediately prior to intranasal corticosteroids or azelastine and may be especially helpful in reducing postnasal drip, sneezing, and congestion.37 A 2007 Cochrane database review found 8 randomized controlled trials in which saline was evaluated in comparison with either no treatment, placebo, as an adjunct to other treatments or against treatments. There was no evidence that saline alone was beneficial in the treatment of chronic rhinosinusitis nor was it more effective than an intranasal corticosteroid. However, there was favorable evidence for saline as an adjunct treatment. The final conclusion was that saline irrigations are a well tolerated with very minor side effects that can be included as a treatment adjunct for chronic rhinosinusitis symptoms.38 In a prospective, randomized controlled trial with 121 adults with chronic nasal and sinus symptoms, Pynnonen et al.39 looked to determine if isotonic sodium chloride nasal irrigations performed with large volume and low positive pressure was more effective than saline sprays at improving quality of life and decreasing medication use. The primary outcomes measured were a change in symptom severity measure by a mean 20-item Sino-Nasal Outcome Test (SNOT-20) score, medication use, and symptom frequency. The outcomes were looked at 3 different time points (2, 4, and 8 weeks). The high volume, low positive pressure group had lower SNOT-20 scores at all time points. They also had a lower frequency of "often or always" nasal symptom reporting compared to the spray group (40% of subjects versus 61%). A significant difference was not found in sinus medication use in either group.39

The exact mechanism of how saline is helpful in allergic rhinitis and rhinosinusitis has not been confirmed but it is postulated that it may improve mucus clearance; remove antigen, inflammatory mediators, or biofilm; enhance ciliary beat; and protect the nasal mucosa. Side

effects from its use are typically minor and consist of burning, irritation, and nausea. There is not an established consensus regarding method of delivery, volume to use, ratio of isotonic to hypertonic, or frequency.1

Investigational therapies

1. Capsaicin

Capsaicin is the chemical contained within the oil of Capsicum pepper and while it is initially irritating to the applied area, it eventually desensitizes the sensory neural fibers. It has been used intranasal to try and decrease nasal hyperreactivity responsible for rhinorrhea, sneezing, and congestion.37 A placebo-controlled studies using intranasal capsaicin in patient with nonallergic, noninfectious perennial rhinitis found a significant and long-term reduction in the visual analogue scale (VAS) scores in the treatment group but no difference objective measures of inflammation such as concentration of leukotriene C4/D4/E4, prostaglandin D2, and tryptase.40

2. Silver nitrate

Topically applied silver nitrate was found to be effective in a trial comparing silver nitrate, flunisolide, and placebo in patients with NAR. Improvement was found in patient reported rhinorrhea, sneezing and nasal congestion.41 Two prospective studies in patients with vasomotor rhinitis also found significant improvement in nasal symptoms.42,43

3. Acupuncture

From a systematic review of complementary and alternative medicine for rhinitis and asthma published in the Journal of Allergy and Clinical Immunology in 2006, the majority of studies on acupuncture were in allergic rhinitis and were not randomized, controlled, or descriptive. There was 1 nonrandomized study in NAR that showed no difference in nasal airflow and symptoms between acupuncture and electrostimulation.44 However, in 2009, a random, placebo-controlled study by Fleckenstein et al.45 was published that showed a significant change in nasal sickness score (NSS, max 27 points) in patients with vasomotor rhinitis treated with acupuncture versus those who had sham laser acupuncture treatment. The treatment group had a NSS that went from 9.3±3.89 to 4.1±3.2 (P<0.001) while the sham groups NSS went from 5.6±2.74 to 3.7±2.4.45

Surgery

After 6-12 months of failed medical therapy (intranasal corticosteroid with azelastine and/or decongestants and/or ipratropium bromide) then surgical options may be considered. It may also be indicated if the patient has comorbid conditions such as nasal obstruction from severe nasal septal deviation or inferior turbinate hypertrophy, adenoidal hypertrophy, or refractory sinusitis.1 Treatment similarities and differences in allergy and nonallergic rhinitis are outlined in Table 3.

Table 3

Treatment regimens for allergic and nonallergic rhinitis

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SUMMARYRhinitis is a prevalent disease worldwide that causes a significant impact on patient quality of life, can affect multiple comorbid conditions, and is a substantial economic burden on society. It is important to note that a majority of rhinitis patients experience significant non-allergic triggers and thus may non-allergic or mixed (allergic and non-allergic) rhinitis. An improved consensus criterion for defining rhinitis subtypes is essential. This will allow for better understanding the prevalence and epidemiology of chronic rhinitis subtypes and for selecting the appropriate study populations to investigate mechanisms and specific therapies of these disorders.

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2. van Cauwenberge P, Bachert C, Passalacqua G, Bousquet J, Canonica GW, Durham SR, Fokkens WJ, Howarth PH, Lund V, Malling HJ, Mygind N, Passali D, Scadding GK, Wang DY. Consensus statement on the treatment of allergic rhinitis. European Academy of Allergology and Clinical Immunology. Allergy. 2000;55:116–134. [PubMed]

3. Benninger M, Farrar JR, Blaiss M, Chipps B, Ferguson B, Krouse J, Marple B, Storms W, Kaliner M. Evaluating approved medications to treat allergic rhinitis in the United States: an evidence-based review of efficacy for nasal symptoms by class. Ann Allergy Asthma Immunol. 2010;104:13–29. [PubMed]

4. Nathan RA. The burden of allergic rhinitis. Allergy Asthma Proc. 2007;28:3–9. [PubMed]

5. Spector SL, Nicklas RA, Chapman JA, Bernstein IL, Berger WE, Blessing-Moore J, Dykewicz MS, Fineman SM, Lee RE, Li JT, Portnoy JM, Schuller DE, Lang D, Tilles SA. Symptom severity assessment of allergic rhinitis: part 1. Ann Allergy Asthma Immunol. 2003;91:105–114. [PubMed]

6. Min YG. The Pathophysiology, Diagnosis and Treatment of Allergic Rhinitis. Allergy Asthma Immunol Res. 2010;2:65–76. [PMC free article] [PubMed]

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9. Broide DH. Allergic rhinitis: Pathophysiology. Allergy Asthma Proc. 2010;31:370–374. [PubMed]

10. Kim D, Baraniuk JN. Neural aspects of allergic rhinitis. Curr Opin Otolaryngol Head Neck Surg. 2007;15:268–273. [PubMed]

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14. Katzung BG, Trevor AJ, Masters SB. Katzung & Trevor's pharmacology: examination & board review. 6th ed. New York: McGraw-Hill; 2002.

15. Levocetirizine (Xyzal) for allergic rhinitis and urticaria. Med Lett Drugs Ther. 2007;49:97–99. [PubMed]

16. Ciprandi G. Treatment of nonallergic perennial rhinitis. Allergy. 2004;59(Suppl 76):16–23. [PubMed]

17. Milgrom H, Biondi R, Georgitis JW, Meltzer EO, Munk ZM, Drda K, Wood CC. Comparison of ipratropium bromide 0.03% with beclomethasone dipropionate in the treatment of perennial rhinitis in children. Ann Allergy Asthma Immunol. 1999;83:105–111. [PubMed]

18. Martin BG, Andrews CP, van Bavel JH, Hampel FC, Klein KC, Prillaman BA, Faris MA, Philpot EE. Comparison of fluticasone propionate aqueous nasal spray and oral montelukast for the treatment of seasonal allergic rhinitis symptoms. Ann Allergy Asthma Immunol. 2006;96:851–857. [PubMed]

19. Esteitie R, deTineo M, Naclerio RM, Baroody FM. Effect of the addition of montelukast to fluticasone propionate for the treatment of perennial allergic rhinitis. Ann Allergy Asthma Immunol. 2010;105:155–161. [PubMed]

20. Cox L, Li T, Nelson H, Lockey R. Allergen immunotherapy: a practice parameter second update. J Allergy Clin Immunol. 2007;120:S25–S85. [PubMed]

21. Mohapatra SS, Qazi M, Hellermann G. Immunotherapy for allergies and asthma: present and future. Curr Opin Pharmacol. 2010;10:276–288. [PMC free article] [PubMed]

22. Frew AJ. Sublingual immunotherapy. N Engl J Med. 2008;358:2259–2264. [PubMed]

23. Chang H, Han DH, Mo JH, Kim JW, Kim DY, Lee CH, Min YG, Rhee CS. Early compliance and efficacy of sublingual immunotherapy in patients with allergic rhinitis for house dust mites. Clin Exp Otorhinolaryngol. 2009;2:136–140. [PMC free article] [PubMed]

24. Kim ST, Han DH, Moon IJ, Lee CH, Min YG, Rhee CS. Clinical and immunologic effects of sublingual immunotherapy on patients with allergic rhinitis to house-dust mites: 1-year follow-up results. Am J Rhinol Allergy. 2010;24:271–275. [PubMed]

25. Di Bona D, Plaia A, Scafidi V, Leto-Barone MS, Di Lorenzo G. Efficacy of sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a systematic review and meta-analysis. J Allergy Clin Immunol. 2010;126:558–566. [PubMed]

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32. Banov CH, Lieberman P. Efficacy of azelastine nasal spray in the treatment of vasomotor (perennial nonallergic) rhinitis. Ann Allergy Asthma Immunol. 2001;86:28–35. [PubMed]

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35. Webb DR, Meltzer EO, Finn AF, Jr, Rickard KA, Pepsin PJ, Westlund R, Cook CK. Intranasal fluticasone propionate is effective for perennial nonallergic rhinitis with or without eosinophilia. Ann Allergy Asthma Immunol. 2002;88:385–390. [PubMed]

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39. Pynnonen MA, Mukerji SS, Kim HM, Adams ME, Terrell JE. Nasal saline for chronic sinonasal symptoms: a randomized controlled trial. Arch Otolaryngol Head Neck Surg. 2007;133:1115–1120. [PubMed]

40. Blom HM, Van Rijswijk JB, Garrelds IM, Mulder PG, Timmermans T, Gerth van Wijk R. Intranasal capsaicin is efficacious in non-allergic, non-infectious perennial rhinitis. A placebo-controlled study. Clin Exp Allergy. 1997;27:796–801. [PubMed]

41. Erhan E, Külahli I, Kandemir O, Cemiloglu R, Yigitbasi OG, Cüreoglu S. Comparison of topical silver nitrate and flunisolide treatment in patients with idiopathic non-allergic rhinitis. Tokai J Exp Clin Med. 1996;21:103–111. [PubMed]

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Treatment trends in allergic rhinitis and asthma: a British ENT surveyRavinder S Natt, 1 Petros D Karkos,2 Davinia K Natt,4 Eva G Theochari,3 and Apostolos Karkanevatos1

Author information ► Article notes ► Copyright and License information ►Go to:

Abstract

Background

Allergic Rhinitis is a common Ear, Nose and Throat disorder. Asthma and Allergic Rhinitis are diseases with similar underlying mechanism and pathogenesis. The aim of this survey was to highlight current treatment trends for Allergic Rhinitis and Asthma.

Method

A questionnaire was emailed to all registered consultant members of the British Association of Otorhinolaryngologists - Head and Neck Surgeons regarding the management of patients with Allergic Rhinitis and related disorders.

Results

Survey response rate was 56%. The results indicate a various approach in the investigation and management of Allergic Rhinitis compatible with recommendations from the Allergic Rhinitis and Its Impact on Asthma guidelines in collaboration with the World Health Organisation.

Conclusion

A combined management approach for patients with Allergic Rhinitis and concomitant Asthma may reduce medical treatment costs for these conditions and improve symptom control and quality of life.

Keywords: Allergic Rhinitis, Asthma, Survey, Questionnaire, AtopyGo to:

BackgroundThe definition of Allergic Rhinitis (AR) was formulated by Hansel in 1929 [1]. It is a symptomatic nasal disorder caused by allergen exposure through an IgE-mediated immune response against allergens. AR can be subdivided into intermittent (symptoms <4 days per week or for <4 weeks) and persistent disease (symptoms >4 days per week or for >4 weeks) and is further characterized according to severity as mild or moderate/severe [2].

The nasal passage and paranasal sinuses are an integral part of the respiratory tract and patients may have rhinitis without sinusitis, but not sinusitis without rhinitis, hence the term rhinitis has been replaced in modern ENT literature by the more accurate term rhinosinusitis [3]. AR and Asthma are linked epidemiologically, pathologically, physiologically and therapeutically and can be considered as a manifestation of a single inflammatory airway syndrome [4]. Most patients with Asthma have rhinitis suggesting the concept of "one airway, one disease" [5]. AR is more prevalent than Asthma and a European population study was reported to have an AR prevalence rate of 25% [6]. AR usually precedes Asthma and can be considered as risk factor for the development of Asthma. Rhinitis exists in up to 80% of Asthma patients and frequently exacerbates Asthma and increases the risk of Asthma attacks, but the prevalence of Asthma in

patients with rhinitis varies from 10 - 40% [7]. AR and Asthma are chronic respiratory diseases that cause major disability worldwide including impaired sleep, school, work and quality of life and are associated with substantial economic costs [8].

The aetiology of AR is multi-factorial and the diagnostic and therapeutic choices remain diverse. The aim of this questionnaire survey was to highlight the treatment trends in the management of AR amongst UK-based otolaryngologists.

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MethodsA questionnaire (Appendix 1) was emailed via ENT UK to the email addresses of all registered consultant members of the British Association of Otorhinolaryngologists - Head and Neck Surgeons (BAO-HNS). Survey recipients were asked 1) about their familiarity with the Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines in collaboration with the World Health Organisation (WHO), 2) about the type of investigations, treatment regimes and follow-up arrangements for AR patients and 3) about whether they give to patients advice leaflets on life style changes including education and allergen avoidance. All participants had the opportunity to answer anonymously.

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ResultsA total of 551 questionnaires were emailed. There were 309 replies (56% response rate). All consultants were familiar with the association between AR and Asthma but only 63% of the respondents were familiar with the ARIA guidelines. Seventy seven (25%) of otolaryngologists managed AR patients of which a 20 - 30% proportion had associated symptoms or a diagnosis of Asthma (Figure (Figure1 1 ).

Figure 1Proportion of Allergic Rhinitis patients that have Asthma.

The commonest investigation requested was skin prick testing (81% of respondents). Only nine consultants (3%) arranged pulmonary spirometry (Figure (Figure2 2 ).

Figure 2Investigations for Allergic Rhinitis.

Fifty six per cent of otolaryngologists preferred the management pathway of starting treatment and then discharging AR patients to General Practitioners (GPs) for further follow-up. However three (1%) consultants managed and subsequently referred AR patients to a respiratory physician (Figure (Figure3 3 ).

Figure 3Management Pathway for Allergic Rhinitis.

In total two hundred and forty (78%) of otolaryngologists provided patient leaflets on life-style changes including education and practical tips on allergens avoidance .(Figure .(Figure4 4 )

Figure 4Treatment for Allergic Rhinitis.Go to:

DiscussionAR is a multi-factorial disease with a worldwide disabling effect on all individuals irrespective of age and ethnic background. In 2001 the ARIA in collaboration with the WHO workshop published guidelines for healthcare professionals in order to highlight the latest updates on the aetiology of AR emphasizing the association between AR and Asthma and proposing a management algorithm [2]. In 2008 a further update incorporated evidence based practice and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group methodology with a focus on the prevention of allergic and chronic respiratory diseases [9].

Risk factors for AR include a combination of environmental and genetic interactions [10]. The diagnosis of AR is based upon a thorough history of allergic symptoms and diagnostic investigations. The European Academy of Allergiology and Clinical Immunology, the US Joint Council of Allergy and Asthma and the WHO recommend the use of skin prick testing for AR, which is preferred by the majority of UK otolaryngologists (81%) [11].

An overwhelming 99% of UK ENT consultants use intra-nasal steroids to treat AR. This trend is supported by several studies demonstrating that intra-nasal steroids are the most efficacious and cost effective first line treatment for AR [12,13].

Allergen specific immunotherapy for AR was first described in 1911 by Noon and involves the administration of a gradually increasing quantity of an allergen extract [14]. Patients are selected with demonstrated specific IgE antibodies to known allergens. In the USA the subcutaneous route is the only licensed route of administration. Interestingly 15% of UK otolaryngologists used sublingual and 5% used subcutaneous forms of immunotherapy. There is increasing evidence supporting the use of allergen immunotherapy in AR. Unlike pharmacotherapy, the clinical benefits are likely to be sustained for many years after discontinuation of treatment [15]. Wilson et al in a cochrane review showed sublingual immunotherapy to be a safe and effective option in managing AR [16]. Furthermore, Calderon et al in a recently published meta-analysis advocate the use of allergen injection immunotherapy as an effective treatment with a low risk of adverse effects in the management of AR [17]. However, further studies are required to evaluate significant differences between these two routes. Allergen specific immunotherapy is not recommended in patients with severe or uncontrolled Asthma because of risk of adverse bronchial reactions [18].

The importance of educating patients or carers with advice leaflets with information regarding AR including allergen avoidance cannot be over emphasised and was actively supported by 78% of responders of this survey. This enables individuals to be actively involved in the management of their disease resulting in an overall improvement in patient satisfaction, treatment compliance and outcomes [19]. Such practice is endorsed by the General Medical Council (GMC) through its guidance on good medical practice for doctors [20].

Interestingly, only 3% of otolaryngologists arranged pulmonary spirometry and 1% of all respondents referred AR patients to a respiratory physician for management of any associated lower respiratory tract pathology. Several studies though have demonstrated that AR patients with no underlying Asthma do have impaired pulmonary function and reversible airway obstruction [21,22]. In addition, studies have revealed that AR is linked to an increased use of Asthma related medical services and that the treatment of either AR or that of Asthma can alleviate the symptoms of the other and hence reduce the number of days off school and work and costs of utilising medical services loss of employment productivity [23,24]. Furthermore, greater awareness of the economic burden of AR would assist healthcare providers in establishing priorities for the allocation of their limited resources and ultimately ensure cost and clinical effective outcomes [25].

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ConclusionThis survey demonstrates as expected a diverse approach to the management of Allergic Rhinitis. An interesting finding of the survey is that despite good evidence on the relationship between Asthma and AR, most otolaryngologists often do no think "outside the specialty", for example they would rarely use spirometry as a diagnostic aid.

A combined treatment strategy of allergen avoidance, pharmacotherapy, immunotherapy and education applied to patients with AR and concomitant Asthma as recommended by the ARIA guidelines may reduce medical treatment costs and improve symptom control and quality of life.

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Conflicts of and Competing interestsThe authors declare that they have no competing interests.

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Authors' contributionsRSN: Primary Author of manuscript. PDK: Assistant Author of manuscript and Editing. EGT: Contribution to Literature Search and Proof Reading. AK: Senior Clinician and contribution to Proof Reading and Editing. DKN: Assisted writing manuscript and designing questionnaire. All authors read and approved the final manuscript.

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APPENDIX 1: Allergic Rhinitis E-mail QuestionnaireDear colleague,

Pease could you complete this survey with your responses and return it by clicking the SUBMIT button below. We thank you for your valuable time in completing this survey.

1. Are you familiar with the association between Allergic Rhinitis and Asthma?

• Yes

• No

2. Are you familiar with the Allergic Rhinitis and its impact on Asthma (ARIA) guidelines in collaboration with the World Health Organisation?

• Yes

• No

3. What proportion of your patients with Allergic Rhinitis have got symptoms or diagnosis of Asthma?

• <10%

• 10 - 20%

• 20 - 30%

• 30 - 40%

• 40 - 50%

• >50%

4. If you suspect Allergic Rhinitis what investigations would you consider (you may tick one, or more of the following)?

• None

• Skin prick test to known allergens

• Serology tests e.g. RAST, IgE

• Peak flow meter (air flow litres/minute)

• Pulmonary spirometry

5. If you suspect Allergic Rhinitis in a patient which of the following management plans would you consider?

• Start treatment and review

• Start treatment and discharge patient to GP for follow-up

• Start treatment and refer to a Respiratory Physician

6. If you suspect Allergic Rhinitis which of the following would you use for treatment (you may tick one, or more of the following)?

• Antihistamine - oral

• Antihistamine - intra-nasal

• Steroid - intra-nasal

• Steroid - intra-bronchial

• Steroid - oral

• Decongestant - oral

• Decongestant - intra-nasal

• Anti-cholinergic (Ipatropium Bromide)

• Anti-leukotriene

• Specific Immunotherapy - sublingual

• Specific Immunotherapy - subcutaneous

7. How long do you prescribe nasal sprays for

• 3 months

• 6 months

• >6 months

8. What is the frequency of nasal spray administration do you prescribe (you may tick one, or more from the following)?

• Two puffs once a day

• Two puffs twice a day

• Other (please specify)

9. Do you provide leaflets for patients about life-style changes including education and avoidance of allergen(s)?

• Yes

• No

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Pre-publication historyThe pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1472-6815/11/3/prepub

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Acknowledgements

Presented at the 22nd Congress of the European Rhinologic Society (ERS) and the 27th

International Symposium of Infection and Allergy of the Nose (ISIAN), Crete, 19th June 2008.

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Allergy. 1929;1:43–70. doi: 10.1016/S0021-8707(29)90083-6. [Cross Ref]2. Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic Rhinitis and its impact of Asthma.

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4. Cauwenberge P, Watelet J, Zele T, Wang D, Toskala E, Durham S. et al. Does rhinitis lead to Asthma? Rhinol. 2007;45:112–121. [PubMed]

5. Bousquet J, Vignola AM, Demoly P. Links between rhinitis and Asthma. Allergy. 2003;58:691–706. doi: 10.1034/j.1398-9995.2003.00105.x. [PubMed] [Cross Ref]

6. Bachau V, Durham SR. Prevalence and rate of diagnosis of Allergic Rhinitis in Europe. Eur Respir J. 2004;24:758–764. doi: 10.1183/09031936.04.00013904. [PubMed] [Cross Ref]

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