This is the protocol for a review and there is no abstract. The objectives are as follows:
To evaluate the effectiveness and safety of oral antihistamines (such as loratadine, desloratadine, cetirizine, levocetirizine, fexofenadine, terfenadine) in patients with SAC.
Description of the condition
Ocular allergy affects up to 40% of the general population (Sing 2007; Sing 2010) and has become increasingly prevalent in the last four decades (Bielory 2000; Davies 1998; Friedlander 1991). The symptoms include intense itching, photophobia (discomfort of light) and lacrimation (secretion of tears). Such symptoms affect daily leisure and work activities of adults and children and, consequently, overall well being and quality of life (Valencio 2007). In severe cases, increases in lesions of the ocular conjunctiva (membrane of the eye that covers the external surface) may occur and can cause ptosis (fallen upper eyelid), corneal ulcer (the absence of epithelium cells, exposing the underlying tissue) and neovascularisation (new blood vessels), with the risk of amblyopia (one eye does not develop fully) and blindness (Nishiwaki-Dantas 2008; Ono 2005). Ocular allergy includes a group of diseases that affect the ocular surface and are associated with a type I hypersensitivity reaction. The most common clinical form is conjunctivitis (inflammation of the conjunctiva), which is usually associated with allergic rhinitis (Sing 2007) and is known as rhinoconjunctivitis (inflammation of the nasal mucous and conjunctiva) (Johanson 2004).
Allergic conjunctivitis is classified as seasonal (SAC), perennial (PAC), atopic (AKC) and vernal (VKC). SAC is the most common form of eye allergy and is characterised by acute unilateral or bilateral itching, tearing and conjunctival hyperaemia (increased blood in the eyes) during the pollination periods of the year. SAC occurs in previously sensitised individuals when exposed to aeroallergens, such as grass and ragweed pollens (Bielory 2000; Valencio 2007). PAC is a chronic year-round allergy, with some occurrence of exacerbations, and is probably associated with house dust mites (Bielory 2000; Bonini 2000; Valencio 2007). AKC is a more severe type of allergic conjunctivitis, occurring most often in the second to third decade of life. Although it has no seasonality, it may worsen in the winter. The symptoms include ocular itching, burning, photophobia and mucous secretion. It may also present as chronic conjunctivitis with scarring, affecting the eyelids and cornea (the clear front covering of the eye), and can be associated with keratoconus (an abnormal cone-shaped protrusion of the cornea) and cataracts (a clouding of the natural lens of the eye). It is estimated that ocular allergy is associated with atopic dermatitis (inflammation of the palpebral skin) in 25% to 50% of cases (Bonini 2000; Cameron 1989; Coyle 1984; Nishiwaki-Dantas 2008; Sing 2007). VKC is a chronic keratoconjunctivitis (inflammation of the cornea and conjunctiva) that is most common in young boys (Katelaris 2003). The patients usually report intense itching and photophobia, with the feeling of a foreign body that is mainly exacerbated during the spring or summer. VKC patients present with hyperaemia and conjunctival oedema (swelling from the excessive accumulation of liquid in the tissue), and moderate mucous secretion. Furthermore, epithelial erosions (the absence of some epithelium cells), shield-shaped corneal ulcers, peripheral neovascularisation and pannus (corneal superficial vascularisation) may appear in VKC (Bonini 2000; Cameron 1989; Coyle 1984; Nishiwaki-Dantas 2008; Sing 2007).
Although the signs and symptoms of SAC are relatively mild to moderate, it is the most common of the allergic eye diseases and can affect daily activities, productivity at work, and performance in school, resulting in economic costs on society (Katelaris 2008; Smith 2005).
Description of the intervention
Several agents have been used in the management of allergic conjunctivitis, including vasoconstrictors (e.g., epinephrine), mast cell stabilisers (e.g., cromoglycate), double-action agents (e.g., olopatadine), non-hormonal anti-inflammatories (e.g., paracetamol), corticosteroids (e.g., dexamethasone), and oral (e.g., desloratadine) and topical (e.g., lodoxamide) antihistamines.
Histamine is one of the main mediators of the allergic reaction and is the result of the contact between allergens and the conjunctival mucosa; its action triggers the initial phase symptoms of allergy, e.g., itching, and releases multiple pro-inflammatory cytokines that promote vasoactive effects (Leonardi 2000). Antihistamines act as reverse agonists of the histaminic receptors, presenting an anti-inflammatory effect (Maichuk 2000), and are classified as H1 (the most used for ocular allergies), H2 and H3 blockers. As a monotherapy, oral antihistamines are used to control the symptoms of allergic conjunctivitis and rhinoconjunctivitis, however the occurrence of side effects cannot be ruled out (Leurs 2002). The first generation of antihistamines (e.g., chlorpheniramine, diphenhydramine, doxylamine and pyrilamine) can present such side effects as drowsiness, sedation, fatigue, headache and memory disorders, in addition to dry eyes and mouth, blurry vision and urinary retention (Bielory 2005; el Cuvilo 2006).
Clinical studies have shown that most oral antihistamines, mainly the second- and third-generation antihistamines (e.g., cetirizine, levocetirizine, loratadine, and desloratadine) present less side effects and reduce ocular itching, tearing and redness of seasonal allergic rhinoconjunctivitis, thus significantly increasing quality of life. When the symptoms are predominantly ocular, treatment with topical antihistamines, such as olopatadine, ketotifen, emedastine and epinastine, seems to be more efficient due to the higher concentration at the site in a short period of time (Abelson 1993; Bielory 2005; el Cuvilo 2006; Grumetto 2002; Hansen 2005; Hingorani 1995; Simons 2004; Sprangler 2003; Timmerman 2000; Torkildsen 2009).
How the intervention might work
The intervention will alleviate the symptoms causing the discomfort of SAC, such as itching (by blocking chemical processes in an allergic reaction), photophobia and the reduction of visual acuity, resulting in an improvement of the daily activities and the overall wellness and quality of life of the patients.
Why it is important to do this review
This systematic review aims to evaluate the effectiveness and safety of oral antihistamines in adults and children with a history of SAC. Numerous treatment options exist for SAC, including artificial tears, hormonal and non-hormonal anti-inflammatories, immunomodulation, conjunctival papilla (lesions of the conjunctiva) surgery and complementary therapy.
A Cochrane systematic review assessing the effectiveness of antihistamines used as adjuncts to topical nasal steroids for intermittent and persistent allergic rhinitis in children reported no effect due to a lack of evidence (Nasser 2010).
To evaluate the effectiveness and safety of oral antihistamines (such as loratadine, desloratadine, cetirizine, levocetirizine, fexofenadine, terfenadine) in patients with SAC.
Criteria for considering studies for this review
Types of studies
We will consider randomised controlled trials (RCTs). Although RCTs are not necessarily a good source of evidence to detect uncommon safety events, we will not perform a safety evaluation through other study designs (e.g., cohort studies).
Types of participants
Adults and children (regardless of gender, age and race) with acute SAC, diagnosed by clinical history or by an allergen-specific IgE antibody exam or eosinophil levels, with or without allergic rhinitis (AR) or asthma, in whom oral antihistamines are being used.
Types of interventions
We will consider the following comparisons.
Intervention group: oral antihistamine drugs, with or without the administration of any topical ocular (i.e., artificial tears) or nasal (i.e., cromoglycate) drugs, or both, prescribed for SAC.
Control group: no intervention, or placebo both topic (tablet, eyedrop, etc) or oral, or both; oral antihistamine drugs alone with or without topic placebo; topical ocular (i.e., artificial tears) or nasal (i.e., cromoglycate) drugs, or both, with or without oral placebo.
We will also consider comparisons between different oral antihistamine drugs as well as any dosage and duration of therapy.
We will exclude studies on topical steroids, complementary medicine and surgery.
Types of outcome measures
The primary outcome will be patient reported symptoms such as itching, tearing, red eye, or discomfort as well as overall change of composite measures of those symptoms. As there will be different tools evaluating symptoms such as visual analogue scale (VAS) we will try to transform the data to common measurements where possible to facilitate meta-analysis. We will assess the outcome from the date of randomisation to four months (season period). We will also collect data and meta-analyse the primary outcome at other commonly reported time points, if possible.
Rhinitis-related symptoms such as sneezing, rhinorrhoea and postnasal drip, pruritus (itching), and nasal congestion measured by any validated tool such as VAS or non-validated instrument, or both.
Need for rescue medication (other oral antihistamines).
Quality of life measures (however defined by study authors).
Adverse events. We will consider any specific adverse effects, systemic or local, and any clinically diagnosed hypersensitivity or other adverse reactions related to the control group (e.g., steroid medication).
We will also collect data about costs as a narrative analysis that can be used by others to be included in a cost-effectiveness study.
Search methods for identification of studies
There will be no language, date or publication status restrictions in the search for trials.
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (latest issue), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to present), EMBASE (January 1980 to present), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to present), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We will not use any date or language restrictions in the electronic search for trials.
See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), LILACS (Appendix 4), mRCT (Appendix 5), ClinicalTrials.gov (Appendix 6) and the ICTRP (Appendix 7).
Searching other resources
We will check the references of potential studies for additional published and/or unpublished papers. We will contact experts in the field for additional citations.
Data collection and analysis
Selection of studies
Two review authors (AK and RED) will independently screen the abstracts identified by the literature search. We will obtain full copies of all potentially or definitely related articles. We will resolve disagreements by consulting with the other review author (MMC). We will document the excluded studies and reasons for exclusion in a table entitled 'Characteristics of excluded studies'. We will include a PRISMA flow chart showing the details of the search results in the review
Data extraction and management
Two authors (AK and MMC) will independently extract data. We will resolve any discrepancies by discussion. We will use a standard data extraction form to extract the following information: characteristics of the study (design, methods of randomisation); participants; interventions; outcomes (types of outcome measures, adverse events) (see Appendix 8 for further information). One author (RED) will enter all data into Review Manager (RevMan 5.2) and a second author (AK) will independently check the data entered.
Assessment of risk of bias in included studies
For the assessment of study quality, we will use the the risk of bias tool as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will use the following six separate criteria.
Low risk of bias: allocation was controlled by a central and independent randomisation unit, sequentially numbered, opaque and sealed envelopes or similar, so that intervention allocations could not have been foreseen in advance of, or during, enrolment.
Uncertain risk of bias: the trial was described as randomised, but the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment.
High risk of bias: if the allocation sequence was known to the investigators who assigned participants, or if the study was quasi-randomised.
Incomplete outcome data
Low risk of bias: the underlying reasons for missing data are unlikely to make treatment effects depart from plausible values, or proper methods have been employed to handle missing data.
Uncertain risk of bias: there is insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data are likely to induce bias on the estimate of effect.
High risk of bias: the crude estimate of effects (eg., complete case estimate) will clearly be biased due to the underlying reasons for missing data, and the methods used to handle missing data are unsatisfactory.
Vested interest bias
Low risk of bias: if the trial's funding did not come from any parties that might have conflicting interests (eg., an antibacterial agent manufacturer), or if any academic, professional, financial, or other benefits to the person responsible for the trial are independent of the direction or statistical significance of the trial results.
Uncertain risk of bias: if the source of funding was not clear, or if it is unclear if the person responsible for the trial stands to benefit according to the direction or statistical significance of the trial results.
High risk of bias: if the trial's source of funding had a conflict of interest, or if any academic, professional, financial, or other benefits to the person responsible for the trial are dependent on the direction or statistical significance of the trial results.
We will assess all trials for risk of bias. If the risk of bias in a trial is judged as 'low' in all the listed above domains, the trial will fall in the 'low risk of bias' group. If the risk of bias in the assessed trials is judged as 'uncertain' or 'high' in one or more of the specified domains, then the trial will fall in the 'high risk of bias' group.
In a first step, information relevant for making a judgement on a criterion will be copied from the original publication into an assessment table. If additional information is available from study authors, this will also be entered in the table along with an indication that this is unpublished information. Two review authors (AK and RED) will independently make a judgment as to whether the risk of bias for each criterion was considered to be 'low', 'uncertain', or 'high'. We will resolve disagreements by discussion.
We will record this information for each included trial in 'Risk of bias' tables in RevMan (RevMan 2012) and summarise the risk of bias for each trial in a summary 'Risk of bias' figure and graph.
Measures of treatment effect
We will process included trial data as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
(a) Binary outcomes
For dichotomous data (e.g., need for rescue medication, assessment of allergen sensitivity in either the eye or nose, and adverse events), we will use the risk ratio (RR) as the effect measure with 95% confidence intervals (CIs).
(b) Continuous outcomes
For continuous data (e.g., quality of life, visual acuity and improvement of global symptoms), we will present the results as mean differences (MDs) with 95% CIs. When pooling data across studies, we will estimate the MD if the outcomes are measured in the same way between trials. We will use the standardised mean difference (SMD) to combine trials that measure the same outcome but use different methods.
(c) Multiplicity issues
We will perform meta-analysis for all outcomes, but only draw a conclusion based on the primary outcome.
Unit of analysis issues
The unit of analysis will be the patient and eyes according to the evaluated outcomes.
Dealing with missing data
An intention-to-treat analysis (ITT) is one in which all the participants in a trial are analysed according to the intervention to which they were allocated, whether they received the intervention or not. For each trial we will report whether or not the investigators stated if the analysis was performed according to the ITT principle. If participants were excluded after allocation, we will report any details provided in full. Therefore, we will perform the analysis on an ITT basis (Newell 1992) whenever possible. Otherwise, we will adopt the per protocol analysis.
Assessment of heterogeneity
We will look for clinical heterogeneity by examination of the study details then test for statistical heterogeneity between trial results using the Chi2 test and the I2 statistic as described in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). We will classify heterogeneity using the following I2 values.
• 0 to 40%: might not be important;
• 30% to 60%: may represent moderate heterogeneity;
• 50% to 90%: may represent substantial heterogeneity; and
• 75% to 100%: considerable heterogeneity.
Assessment of reporting biases
Apart from assessing the risk of selective outcome reporting considered under Assessment of risk of bias in included studies, we will assess the likelihood of potential publication bias using funnel plots, provided that there are at least eight trials. As small studies in a meta-analysis tend to show larger treatment effects, we will consider other causes, including: selection biases, poor methodological quality, heterogeneity, artefactual and chance.
Data analysis will follow the guidelines in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). We will calculate pooled estimates using the random-effects model for more than two studies. We will attempt to quantify the proportion of variability within included randomised studies that is explained by heterogeneity using the I2 statistic (Higgins 2002).
Subgroup analysis and investigation of heterogeneity
In the case of excessive clinical heterogeneity (I2 > 50%), we will use subgroup analysis to pool the results. Subgroup analyses are secondary analyses in which the participants are divided into groups according to shared characteristics, and outcome analyses are conducted to determine if any significant treatment effect occurs according to that characteristic. If data permit, we will carry out the following subgroup analyses.
Ages: adults (> or equal to 18 years to 65 years) versus older adults (> than 65 years) versus children (up to 17 years).
Different oral antihistamine drugs (e.g., loratadine versus cetirizine).
We will perform the Chi2 test for subgroup differences set at a P value of 0.05.
We will perform a sensitivity analysis after the original statistical analysis to examine the effects of different trials. We will include the following factors in the sensitivity analysis, separating studies according to:
trials with high risk of bias; and
trials with rates of withdrawal larger than or equal to 20%.
The Cochrane Eyes and Vision Group (CEVG) created, and will execute the electronic search strategies. We acknowledge the support of Anupa Shah and Augusto Azuara-Blanco in the preparation of the protocol and thank Catey Bunce and Senthil Maharajan for their comments on the protocol.
The views expressed in this publication are those of the authors and not necessarily those of the NIHR, NHS or the Department of Health.
Appendix 1. CENTRAL search strategy
#1 MeSH descriptor: [Conjunctivitis, Allergic] explode all trees
#3 pollen near/3 allerg*
#5 hay near/2 fever
#6 #1 or #2 or #3 or #4 or #5
#7 ((antihistamin* or anti-histamin*) near/4 oral*)
#8 MeSH descriptor: [Loratadine] explode all trees
#19 MeSH descriptor: [Astemizole] explode all trees
#21 MeSH descriptor: [Chlorpheniramine] explode all trees
#23 MeSH descriptor: [Triprolidine] this term only
#28 MeSH descriptor: [Pseudoephedrine] this term only
#36 #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35
#37 #6 and #36
Appendix 2. MEDLINE(OvidSP) search strategy
1. randomized controlled trial.pt.
2. (randomized or randomised).ab,ti.
9. exp animals/
10. exp humans/
11. 9 not (9 and 10)
12. 8 not 11
13. conjunctivitis, allergic/
15. (pollen adj3 allerg$).tw.
17. (hay adj2 fever).tw.
19. ((antihistamin$ or anti-histamin$) adj4 oral$).tw.
46. N-acetyl-aspartyl glutamic acid.tw.
50. 18 and 49
51. 12 and 50
The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville et al (Glanville 2006).
Appendix 3. EMBASE (OvidSP) search strategy
1. exp randomized controlled trial/
2. exp randomization/
3. exp double blind procedure/
4. exp single blind procedure/
7. (animal or animal experiment).sh.
9. 7 and 8
10. 7 not 9
11. 6 not 10
12. exp clinical trial/
13. (clin$ adj3 trial$).tw.
14. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
15. exp placebo/
18. exp experimental design/
19. exp crossover procedure/
20. exp control group/
21. exp latin square design/
23. 22 not 10
24. 23 not 11
25. exp comparative study/
26. exp evaluation/
27. exp prospective study/
28. (control$ or prospectiv$ or volunteer$).tw.
30. 29 not 10
31. 30 not (11 or 23)
32. 11 or 24 or 31
33. exp allergic conjunctivitis/
35. (pollen adj3 allerg$).tw.
37. (hay adj2 fever).tw.
39. ((antihistamin$ or anti-histamin$) adj4 oral$).tw.
77. n acetylaspartic acid/
78. N-acetyl-aspartyl glutamic acid.tw.
82. 38 and 81
83. 32 and 82
Appendix 4. LILACS search strategy
loratadine OR desloratadine OR cetirizine OR levocetirizine OR fexofenadine OR terfenadine OR bilastine OR ebastine OR emedastine OR rupatadine OR astemizole OR chlorpheniramine OR triprolidine OR acrivastine OR azelastine OR ketotifen OR pseudoephedrine OR oxatomide OR mizolastine OR acetylaspartic OR glutamic OR NAAGA OR mequitazine and allergic conjunctivitis
Appendix 5. metaRegister of Controlled Trials search strategy
(Tablet OR Oral) AND Allergic Conjunctivitis
Appendix 6. Clinicaltrials.gov search strategy
(Tablet OR Oral) AND Allergic Conjunctivitis
Appendix 7. ICTRP search strategy
Allergic Conjunctivitis = Condition AND Tablet OR Oral = Intervention
Appendix 8. Data on study characteristics
| Heading in table in Revman|| Subheadings for CEVG reviews|| Comment|
| Methods||Study design|
· Parallel group RCT i.e. people randomised to treatment
· Paired eye or intra-individual RCT i.e. eyes randomised to treatment
· Cluster RCT i.e. communities randomised to treatment
· Cross-over RCT
· Other, specify
| ||Eyes||· One eye included in study o Specify how eye selected · Two eyes included in study, both eyes received same treatment o Briefly specify how analysed (best/worst/average/both and adjusted for within person correlation/both and not adjusted for within person correlation) o Specify if mixture one eye and two eye · Two eyes included in study, eyes received different treatments (pair matched) o Specify if correct pair-matched analysis done|
| Participants||Country|| |
| ||Setting|| |
| ||Number of participants|| |
| ||Number of men|| |
| ||Number of women|| |
| ||Average age|| |
| ||Age range|| |
| ||Ethnic group|| |
| ||Inclusion criteria|| |
| ||Exclusion criteria|| |
|“Provide sufficient information to enable users of the review to assess the applicability of the intervention to their own setting, and if possible in a way that allows the intervention to be replicated.” MECIR R65 “If a study is included with more than two intervention arms, restrict comments on any irrelevant arms to a brief comment in the table of ‘Characteristics of included studies’.” MECIR R70|
| Outcomes||List||“Provide clear and consistent information about outcomes measured (or reported), how they were measured and the times at which they were measured”. MECIR R66|
| Notes||Date conducted||Specify dates of recruitment of participants mm/yr to mm/yr|
| ||Sources of funding|| |
| ||Declaration of interest||“Include details of any declarations of interest among the primary researchers. “ MECIR R69|
Contributions of authors
Conceiving the review: Cochrane Eyes and Vision Group (CEVG) and Amélia Kamegasawa (AK).
Co-ordinating the review: Regina El Dib (RED).
Writing the protocol: AK and RED.
Responded to comments from peer reviewers and the editorial base: AK, RED and Mauricio M Chaoul (MMC).
Declarations of interest
AK, MMC and RED have no known conflict of interests.