Topical nasal corticosteroids versus oral antihistamines for allergic rhinitis

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the relative efficacy of currently available intranasal corticosteroids compared to that of currently available oral antihistamines in adults and children for both seasonal and/or perennial allergic rhinitis, in terms of total and individual nasal and ocular symptoms.

Background

Description of the condition

Allergic rhinitis is a symptomatic disorder of the nose induced after allergen exposure and due to an IgE‐mediated inflammation of the membranes lining the nose (ARIA 2008). This chronic disease is characterised by nasal itch, sneezing, watery and mucous rhinorrhoea (watery nasal discharge) and nasal obstruction. It is the most frequent form of non‐infectious rhinitis and is associated with an IgE‐mediated immune response against allergens. The condition is often accompanied by allergic conjunctivitis (inflammation of the eye).

Over 500 million people suffer from this disease worldwide. The prevalence of allergic rhinitis has increased over the last two decades, mainly in countries with a Western lifestyle, and affects between 20% and 30% of adults and up to 40% to 50% of children (Asher 2006). Allergic rhinitis causes major illness and disability, and affects social life, sleep, school (Walker 2007) and work productivity. The economic impact of allergic rhinitis is substantial (ARIA 2008), affecting both individual patients and society as a whole.

Allergic rhinitis is a multifactorial disease with genetic as well as environmental factors influencing disease development. The aeroallergens implicated in allergic rhinitis are classified as indoor (e.g. mites, pets, insects, moulds) or outdoor (e.g. pollens, moulds). Allergic rhinitis has traditionally been classified as seasonal or perennial, based on the duration of exposure to the allergens.

Allergic rhinitis is characterised by an inflammatory infiltrate made up of different cells, such as eosinophils, T cells and mast cells. After allergen exposure, the sensitised individual presents an immediate response (early phase), in which histamine and other mediators are released from mast cells in the nasal mucosa, causing symptoms such as sneezing, itching, rhinorrhea and nasal congestion. A second phase (late phase), characterised by cellular infiltrate, may occur four to 12 hours afterwards, causing mainly nasal congestion. The symptoms of allergic rhinitis are currently considered to be caused mainly by the accumulation and activation of infiltrating cells, which release mediators and cytokines and result in allergic inflammation (ARIA 2008).

Treatment guidelines have been issued by the ARIA (Allergic Rhinitis and its Impact on Asthma) WHO expert panel and recently updated (ARIA 2008). The ARIA document is not intended to be a standard‐of‐care document for individual countries. It is provided as a basis for physicians, healthcare professionals and organisations involved in the treatment of allergic rhinitis in various countries to facilitate the development of relevant local standard‐of‐care documents for their patients. The treatment of allergic rhinitis includes allergen avoidance (when possible), pharmacological treatment and immunomodulation (allergen specific immunotherapy). Depending on the subdivision and severity of allergic rhinitis, a stepwise therapeutic approach is proposed and based on randomised controlled trials. Most trials were carried out before the new classification of allergic rhinitis was made and are therefore reported in terms of seasonal and perennial allergic rhinitis. Medications used for allergic rhinitis are most commonly administered intranasally or orally. Intranasal/topical corticosteroids and oral H1‐antihistamines are considered the first line therapies in patients with moderate to severe allergic rhinitis.

Description of the intervention

Second generation oral antihistamines are often a first choice treatment for allergic rhinitis when they are available and affordable, and are administered in tablet form or in syrup for children. Topical corticosteroids are administered via a nasal spray. Both treatments are suggested to be effective in reducing all nasal symptoms. In clinical practice, compliance, drug preference, drug availability and potential side effects should be considered.

How the intervention might work

Antihistamines bind to H1‐histamine receptors, representing the major mode of action. Antihistamines may also have other anti‐allergic properties, but the extent of these effects is not completely understood.

The effect of intranasal corticosteroids is based on local activity. They can suppress many stages of the allergic inflammatory process.

Why it is important to do this review

The efficacy of the most commonly used medications (oral antihistamines and intranasal corticosteroids) may differ between patients. Moreover, the preferential use of one drug class rather than the other is not clearly stated in the ARIA document. This review will approach this issue.

A meta‐analysis performed by Weiner et al (Weiner 1998) has evaluated the efficacy of oral antihistamines versus intranasal corticosteroids in randomised controlled trials published between 1966 and 1997. In this review, eight out of the 16 studies involved cardiotoxic antihistamines which have since been withdrawn worldwide. During the last decade, more potent and specific intranasal corticosteroids and new second generation antihistamines have been developed. A systematic review and meta‐analysis evaluating the comparative effect of currently available intranasal corticosteroids versus oral antihistamines in adults and children for the treatment of seasonal and perennial allergic rhinitis is therefore warranted. 

Objectives

To evaluate the relative efficacy of currently available intranasal corticosteroids compared to that of currently available oral antihistamines in adults and children for both seasonal and/or perennial allergic rhinitis, in terms of total and individual nasal and ocular symptoms.

Methods

Criteria for considering studies for this review

Types of studies

Double‐blind randomised controlled trials (RCTs) of currently available oral antihistamines versus intranasal corticosteroids for seasonal and perennial allergic rhinitis.

Types of participants

Adults and children with allergic rhinitis due to seasonal or perennial allergens. Allergy must be proven using an objective test such as a positive skin prick test or high circulating levels of allergen‐specific IgE antibody.

Types of interventions

Currently available oral antihistamines alone versus currently available intranasal corticosteroids alone.

Types of outcome measures

Primary outcomes

• Total nasal symptom score (any scores from validated daily or weekly diaries or visual analogue scales).

Secondary outcomes

• Individual nasal symptoms (any appropriate measures of rhinorrhoea, nasal obstruction, sneezing, nasal itching).

• Individual ocular symptoms (any appropriate measures of red, watery and/or itchy eyes).

• Total ocular symptom score (any scores from validated daily or weekly diaries or visual analogue scales).

• Comparative health economic data (Quality Adjusted Life Years, QALYs).

• Comparative assessment of rhinoconjunctivitis quality of life (e.g. validated Juniper's questionnaire (Juniper 1991)).

Search methods for identification of studies

We will conduct systematic searches for randomised controlled trials. There will be no language, publication year or publication status restrictions. We may contact original authors for clarification and further data if trial reports are unclear, and we will arrange translations of papers where necessary.

Electronic searches

Published, unpublished and ongoing studies will be identified by searching the following databases from their inception: the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, current issue); PubMed; EMBASE; CINAHL; LILACS; KoreaMed; IndMed; PakMediNet; CAB Abstracts; Web of Science; BIOSIS Previews; CNKI; mRCT (Current Controlled Trials); ClinicalTrials.gov; ICTRP (International Clinical Trials Registry Platform) and Google Scholar.

Subject strategies for databases will be modelled on the search strategy designed for CENTRAL (see Appendix 1). Where appropriate, we will combine subject strategies with adaptations of the highly sensitive search strategy designed by the Cochrane Collaboration for identifying randomised controlled trials and controlled clinical trials (as described in theCochrane Handbook for Systematic Reviews of Interventions Version 5.0.1, Box 6.4.b. (Handbook 2008)).

Searching other resources

The primary author of each study will be contacted to identify additional published and unpublished studies. The bibliography of each paper and of other published reviews will be checked for further references. We will search PubMed; TRIPdatabase; NHS Evidence ‐ ENT and Audiology; and Google to retrieve existing reviews.

We will search abstracts of relevant conferences and identify other trials through discussion with specialist allergist colleagues and professional acquaintances with an interest in the area to enquire whether they are aware of any unpublished or ongoing trials meeting the selection criteria.

We will consider studies published in languages other than English if the translated abstract indicates that the study is a randomised controlled trial of the comparative efficacy of currently available oral antihistamines versus currently available intranasal corticosteroids. We will use translators provided by the Cochrane ENT Group.

Data collection and analysis

Selection of studies

Two independent authors (PR, PD) will check titles and abstracts identified from the searches. All authors will obtain the full text of all studies of possible relevance for assessment. The authors (PR, PD) will read all abstracts and decide which trials meet the inclusion criteria. Any disagreement will be resolved by discussion between the authors (PR, PD) and the third author (MC) for arbitration where necessary. We will contact authors for clarification where necessary. We will seek further information from study authors when needed. The selected studies will then be further evaluated for methodological quality to select those suitable for meta‐analysis.

Data extraction and management

Each of the suitable reports will be read in detail by MC, PR and PD and relevant details will be transferred on to a standard data extraction sheet (covering study type and methodology; number and description of participants; details of type, dosage and duration of intervention; type, timing and measurement method of outcomes).

Assessment of risk of bias in included studies

PR and PD will independently undertake assessment of the risk of bias of the included trials, with the following to be taken into consideration as guided by theCochrane Handbook for Systematic Reviews of Interventions (Handbook 2008):

• sequence generation;

• allocation concealment;

• blinding;

• incomplete outcome data;

• selective outcome reporting; and

• other sources of bias.

We will use the Cochrane 'Risk of bias' tool in RevMan 5, which involves describing each of these domains as reported in the trial and then assigning a judgement about the adequacy of each entry. This involves answering a pre‐specified question whereby a judgement of 'Yes' indicates low risk of bias, 'No' indicates high risk of bias, and 'Unclear' indicates unclear or unknown risk of bias.

Measures of treatment effect

We will use Review Manager (RevMan 5) (RevMan 2008) for data analysis and quantitative data synthesis.

For continuous data, we will calculate individual and pooled statistics as mean difference (MD) and/or standardised mean difference (SMD) with 95% confidence intervals (CI). We will give consideration to the appropriateness of meta‐analysis in the presence of significant clinical or statistical heterogeneity.

Dealing with missing data

We will include descriptive information on participants missing due to drop‐out, whether there was an intention‐to‐treat or per‐protocol analysis, and missing statistics.

Assessment of heterogeneity

We will test for heterogeneity using the I² statistic and significant heterogeneity will be assumed if the I² is greater than 40% (i.e. more than 40% of the variability in outcome between trials could not be explained by sampling variation) (Handbook 2008). Any statistical or clinical heterogeneity will be explored using sensitivity or subgroup analysis (see below).

Assessment of reporting biases

Quantitative analyses of outcomes will be, wherever possible, on an intention‐to‐treat basis. We will assess for evidence of publication bias graphically using funnel plots and proper statistics (Handbook 2008).

Data synthesis

We will use a fixed‐effect model in the absence of statistical heterogeneity and a random‐effects model if such heterogeneity is likely.

Subgroup analysis and investigation of heterogeneity

In the event of uncovering significant heterogeneity, we will investigate this by undertaking subgroup analyses. Our subgroups of interest are:

• allergen type: seasonal, perennial;

• age of participants: up to six years, six to 12, 12 to 18 or over;

• treatment duration: 0 to six months, seven to 12 months, more than 12 months;

• treatment dose: therapeutic recommended dose, higher experimental dose;

• disease severity: mild versus moderate‐severe;

• type of intervention: double‐dummy or not;

• type of allergen exposure: natural versus experimental; and

• quality of life.

Sensitivity analysis

We will carry out sensitivity analyses, based on the exclusion of a) small studies and b) low quality studies, to assess the robustness of the conclusions, if sufficient studies are available.

Appendices

Appendix 1. Search strategy for CENTRAL

#1 MeSH descriptor Rhinitis explode all trees #2 rhiniti* OR rhinoconjunctivitis OR SAR OR PAR #3 hayfever OR hay NEXT fever OR pollinosis OR pollenosis #4 (allerg* OR hypersensitiv*) NEAR (cat* OR dander OR dust* OR mite* OR dog* OR ragweed OR pollen OR grass* OR cedar OR alder OR willow OR birch OR mugwort OR tree* OR weed* OR perennial* OR season* OR spring OR summer OR nose OR nasal) #5 (#1 OR #2 OR #3 OR #4) #6 MeSH descriptor Steroids explode all trees #7 MeSH descriptor Anti‐Inflammatory Agents explode all trees #8 MeSH descriptor Anti‐Inflammatory Agents, Non‐Steroidal explode all trees #9 (#7 NOT #8) #10 (steroid* OR corticosteroid* OR glucocorticoid* OR corticoid*) #11 (beclomethasone NEXT dipropionate OR budesonide OR flunisolide) #12 (fluticasone NEXT propionate OR fluticasone NEXT furoate OR mometasone NEXT furoate OR triamcinolone NEXT acetonide) #13 #6 or #9 or #10 or #11 or #12 #14 #5 and #13 #15 MeSH descriptor Administration, Topical explode all trees #16 MeSH descriptor Administration, Intranasal explode all trees #17 (spray OR aerosol OR intranasal* OR intra‐nasal OR topical*) #18 #15 or #16 or #17 #19 #14 and #18 #20 MeSH descriptor HISTAMINE ANTAGONISTS explode all trees #21 (histamine NEXT antagonist*) #22 antihistamin* #23 (acrivastine* OR cetirizine* OR chlorpheniramine* OR chlorphenamine* OR clemastine* OR cyproheptadine* OR cyclizine* OR doxylamine OR desloratadine* OR dexbrompheniramine* OR dexchlorpheniramine* OR dimenhydrinate* OR diphenhydramine* OR diphenylpyraline* OR meclizine* OR mequitazine* OR mizolastine* OR oxatomide* OR pheniramine* OR promethazine* OR pyrilamine* OR mepyramine* OR hydroxyzine* OR ketotifen*) #24 (ebastine* OR fexofenadine* OR levocetirizine* OR loratadine* OR desloratadine OR cetirizine) #25 #20 OR #21 OR #22 OR #23 OR #24 #26 #5 AND #25 #27 MeSH descriptor Administration, Oral explode all trees #28 (oral* OR tablet*) #29 #27 OR #28 #30 #26 AND #29 #31 #19 AND #30

What's new

Date	Event	Description
8 March 2017	Amended	Protocol withdrawn March 2017 as review project has not been completed within necessary timescales.

Contributions of authors

Conceiving the review: Moises Calderon (MC), Pascal Demoly (PD) Co‐ordinating the review: MC Undertaking manual searches: Pablo Rodriguez del Rio (PR), PD Screening search results: MC, PR, PD Organising retrieval of papers: MC Screening retrieved papers against inclusion criteria: PR, PD Appraising quality of papers: MC, PR, PD Abstracting data from papers: PR, PD Writing to authors of papers for additional information: MC, PD Providing additional data about papers: MC, PD Obtaining and screening data on unpublished studies: MC, PD Data management for the review: MC, PR, PD Entering data into Review Manager (RevMan 5): MC, PR, PD RevMan statistical data: MC, PR, PD Double entry of data: MC, PR, PD Interpretation of data: MC, PD Statistical analysis: MC, PR, PD Writing the review: MC, PR, PD Guarantor for the review: MC Person responsible for reading and checking review before submission: MC

Declarations of interest

The three authors report no present or past affiliations or other involvement in any organisation or entity with an interest in this review that might lead to a real or perceived conflict of interest.

Notes

Protocol withdrawn March 2017 as review project has not been completed within necessary timescales.

Withdrawn from publication for reasons stated in the review