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Cochrane Database of Systematic Reviews

Allergen injection immunotherapy for perennial allergic


rhinitis (Protocol)

Calderon MA, Carr VA, Jacobson M, Sheikh A, Durham S

Calderon MA, Carr VA, Jacobson M, Sheikh A, Durham S.


Allergen injection immunotherapy for perennial allergic rhinitis.
Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD007163.
DOI: 10.1002/14651858.CD007163.

www.cochranelibrary.com

Allergen injection immunotherapy for perennial allergic rhinitis (Protocol)


Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Allergen injection immunotherapy for perennial allergic rhinitis (Protocol) i


Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]

Allergen injection immunotherapy for perennial allergic


rhinitis

Moises A Calderon1 , Vicky A Carr2 , Mikila Jacobson3 , Aziz Sheikh4 , Stephen Durham5

1 Department of Allergy and Respiratory Medicine, Royal Brompton Hospital, London, UK. 2 Allergy Education for Health, Warwick,

UK. 3 Allergy and Clinical Immunology, Imperial College, South Kensington Campus, London, UK. 4 Division of Community Health
Sciences: GP section, The University of Edinburgh, Edinburgh, UK. 5 Department of Allergy and Respiratory Medicine , Royal
Brompton Hospital, London, UK

Contact address: Moises A Calderon, Department of Allergy and Respiratory Medicine, Royal Brompton Hospital, Imperial College
School of Medicine at the National Heart and Lung Institute, London, SW3 6LY, UK. m.calderon@imperial.ac.uk.

Editorial group: Cochrane ENT Group.


Publication status and date: Edited (no change to conclusions), published in Issue 1, 2010.

Citation: Calderon MA, Carr VA, Jacobson M, Sheikh A, Durham S. Allergen injection immunotherapy for perennial allergic rhinitis.
Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD007163. DOI: 10.1002/14651858.CD007163.

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate the effectiveness and safety of injection immunotherapy in treating perennial allergic rhinitis.

BACKGROUND 2001). Perennial (or persistent) allergic rhinitis is thought to make


up around 29% of all incidences of allergic rhinitis in Europe
Allergic rhinitis is the most common of the allergic diseases and (Bauchau 2005). It is defined by the presence of one or more of
affects around 15% to 20% of the population of the western world the following symptoms: nasal mucus secretion, nasal blockage,
(Bousquet 2001). The prevalence of allergic rhinitis has increased nasal itching or sneezing (Saleh 2007).
in recent decades, with a threefold increase in allergic rhinitis di-
agnoses in children in the UK (Gupta 2007). Allergic rhinitis is The mechanisms that lead to the symptoms of allergic rhinitis are
traditionally described as being either seasonal (triggered by allergy well known. Specific antibodies are bound to high affinity IgE
to grass and tree pollens, and some moulds) or perennial (caused receptors on the surface of mast cells in the nasal mucosa. Upon
by allergy to house dust mites, pet danders, and some moulds). allergen exposure, these antibodies are cross-linked and the mast
However, many individuals suffer allergic symptoms after expo- cells degranulate, releasing histamine, prostaglandins and other
sure to a range of aero-allergens and therefore symptoms are com- inflammatory mediators. This reaction, which is a type I hyper-
monly not limited to being either seasonal or perennial. The ARIA sensitivity reaction (Gell 1963), is responsible for the immediate
report ’Allergic rhinitis and its impact on asthma’ recognises this and allergic symptoms. Specific IgE production is also triggered by t-
suggests that sufferers should be classified as having either inter- lymphocytes, which produce and recruit eosinophils and other
mittent symptoms (occurring for less than four days per week, for pro-inflammatory mediators responsible for the late or delayed
less than four weeks) or persistent symptoms (occurring for more phase of the allergic response, which typically occurs six to eight
than four days per week and for more than four weeks) (Bousquet hours after initial allergen exposure (Lund 1994).
Allergen injection immunotherapy for perennial allergic rhinitis (Protocol) 1
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Diagnosis of allergy is dependent on a clinical history indicative and meta-analyses to be effective in reducing symptom scores and
of allergy, supported by a diagnostic test to confirm an IgE medi- medication use in patients with allergic rhinitis. (Calderon 2007;
ated cause. IgE mediated conditions are usually confirmed by skin Ross 2000).
prick tests (SPT) or by measuring the specific IgE in the serum
(radio-allergosorbant or RAST test) in clinical practice. During The immunological mechanisms responsible for successful aller-
skin prick tests a small droplet of an allergen extract is placed on gen immunotherapy probably involve both the generation of tol-
the skin, usually the extensor surface of the forearm. The skin is erance toward the responsible allergen source and a shift in the
then pricked through the droplet with a specially designed lancet, balance between the allergic Th2 and non-allergic Th1 allergic
introducing a small amount of the extract beneath the skin. Com- phenotype (Robinson 2004).
mon aero-allergen extracts are usually included and also positive
It is important, as with all medical treatments, to consider any side
and negative controls to ensure quality and reliability. If specific
effects or adverse reactions that may occur. Side effects from subcu-
IgE is present a small wheal appears in the skin, which is measured
taneous immunotherapy can be both local and systemic. Swelling
after 15 minutes. There are other methods of allergy diagnosis,
at injection sites is described in many patients. While this can be
many of which are employed during research studies and where
troublesome, it is rarely severe. Systemic reactions vary in severity
diagnosis is in doubt, or not possible using conventional methods.
and range from relatively mild symptoms such as rhinitis to life
These include intradermal or cutaneous testing and bronchial and
threatening symptoms involving severe asthma and anaphylaxis.
conjunctival provocation tests (Durham 2006).
A four-point scale for classifying systemic reactions has been pro-
The management of allergic rhinitis includes avoidance measures. posed in the position paper of the European Academy of Allergol-
However, there is increasing evidence that these measures do not ogy and Clinical Immunology (Malling 1993). Grade 1 reactions
have a significant effect on allergic rhinitis symptoms, particularly include mild, non-specific symptoms and anaphylaxis is given a
in house dust mite allergy (Sheikh 2007; Terreehorst 2003). Phar- grade 4.
macological management in both adults and children is based on a
combination of topical nasal corticosteroids and long-acting, non- The risk of anaphylaxis is supported by a report published by
sedating antihistamines (Al-Sayyad 2007; Bousquet 2001). the British Committee for the Safety of Medicines (CSM 1986)
investigating the safety of subcutaneous immunotherapy, which
For some patients, treatment with a combination of antihistamines suggested that some limitations should be considered or enforced
and topical nasal corticosteroids does not adequately control symp- when initiating treatment and treating patients. The report discov-
toms. One study, investigating symptom control in patients with ered that 26 fatalities had occurred in the United Kingdom since
hay fever in the United Kingdom, found that 62% of sufferers 1957. It was after publication of this report that it was decided
treated with combination treatment still experienced troublesome that use should be limited to specialist practitioners in designated
symptoms and described symptom control as only partial or poor clinics with full resuscitation facilities and that patients should be
(White 1998). Many patients also state that allergy medications observed for up to one hour after treatment. It was also recom-
can provoke unwanted side effects (Juniper 2005) and are con- mended that the treatment should not be administered to patients
cerned about the effects of long-term use of pharmacotherapy, re- with asthma, to people receiving treatment with beta-blocker ther-
sulting in patients being reluctant to use them (Malling 1993). For apy or to those suffering from significant concurrent illness.
this group of patients, where first line treatment is deemed to have
failed, allergen immunotherapy should be considered (Bousquet A recent Cochrane systematic review and meta-analysis (Calderon
1998). 2007) has shown that specific allergen injection immunotherapy
in suitably selected patients with seasonal allergic rhinitis results
Allergen immunotherapy can be delivered by subcutaneous injec- in a significant reduction in symptom scores and medication use.
tion, nasal, oral or sublingual routes. Subcutaneous injections are This review aims to evaluate the safety and efficacy of injection
the most common mode of delivery, although the results of a re- immunotherapy for the treatment of perennial allergic rhinitis.
cent systematic review and meta-analysis found that the sublin-
gual route is effective in reducing both symptoms experienced and
the amount of medication sufferers need to alleviate symptoms
(Wilson 2003). OBJECTIVES
Allergen immunotherapy by injection (also known as hyposen- To evaluate the effectiveness and safety of injection immunother-
sitisation or desensitisation) consists of a course of injections of apy in treating perennial allergic rhinitis.
increasing doses of allergen extract, usually given weekly. Once a
maintenance dose is reached, this dose is then repeated monthly
for three to five years (Bousquet 1998; Durham 1999; Frew 1993).
The treatment has been shown in published systematic reviews METHODS

Allergen injection immunotherapy for perennial allergic rhinitis (Protocol) 2


Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Criteria for considering studies for this review Search methods for identification of studies
We will search the Cochrane Ear, Nose and Throat Disorders
Group Trials Register, the Cochrane Central Register of Con-
Types of studies trolled Trials (CENTRAL) (The Cochrane Library, current is-
Randomised, double blind, placebo controlled trials. sue), MEDLINE (1950 onwards), EMBASE (1974 onwards),
CINAHL (1982 onwards), AMED (1985 onwards), LILACS,
KoreaMed, IndMed, PakMediNet, ZETOC, Cambridge Scien-
Types of participants tific Abstracts (Conference Proceedings Database), ISI Proceed-
Patients suffering from perennial allergic rhinitis due to house dust ings (Web of Science), IMEMR (Index Medicus for WHO East-
mite allergy, pet dander allergy, mould allergy or any combination. ern Mediterranean Region), IMSEAR (Index Medicus for WHO
Children and adults will be included. Allergy must be proven using South-East Asian Region), NRR (the National Research Register),
an objective test such as a skin prick test or specific IgE test (such UKCRN (the UK Clinical Research Network Portfolio Database),
as the radioallergosorbant test (RAST)) or both. ICTRP (the World Health Organization International Clinical
Trials Registry Platform), ReFeR (the Research Findings Register)
and mRCT (the metaRegister of Controlled Trials).
Types of interventions The Cochrane Central Register of Controlled Trials (CENTRAL)
will be searched using the terms:
Multiple (defined as being three or more) injections of high-dose
#1 RHINITIS single term (MeSH)
immunotherapy with standardised single allergen extracts com-
#2 RHINITIS ALLERGIC PERENNIAL single term (MeSH)
pared with placebo treatment. High-dose immunotherapy will be
#3 (allerg* OR hypersensitiv*) NEAR (rhiniti* OR rhinopath* OR
defined as being when the maintenance dose contains more than
nose OR nasal OR cat* OR fur OR hair* OR dander OR dust* OR
5 micrograms of major allergen per millilitre.
mite* OR pet* OR dog* OR cockroach* OR mould* OR mold*
OR perennial* OR persist* OR nonseasonal* OR respiratory)
Types of outcome measures #4 #1 OR #2 OR #3
#5 (seasonal* NEAR allerg* OR seasonal* NEAR rhinitis OR
pollinosis OR pollen* OR pollen NEAR allerg* OR grass NEAR
allerg* OR hay NEXT fever OR hayfever):ti
Primary outcome measures
#6 #4 NOT #5
#7 (non NEXT seasonal* NEAR (allerg* OR rhiniti*)):ti
#8 #6 OR #7
1. Symptoms #9 DESENSITIZATION, IMMUNOLOGIC single term
• Symptom scores - typically collected using symptom diaries (MeSH)
• Daily patient-completed visual analogue scores #10 ALLERGENS [im] single term (MeSH)
#11 ALLERGENS [tu] single term (MeSH)
Preference will be given to formally validated symptom scores #12 ALLERGENS [ad] single term MeSH)
wherever possible. #13 IMMUNOTHERAPY single term (MeSH)
#14 DOSE RESPONSE RELATIONSHIP, IMMUNOLOGIC
single term (MeSH)
2. Clinical
#15 immunotherap* OR immunomodulat* OR immune NEAR
• Medication use therap* OR immunologic* NEAR respons* OR desensiti* OR
• Rhinoconjunctivitis quality of life hyposensiti* OR subcutaneous*
• Adverse reactions: local (including swelling or itching to #16 #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15
injection site) and systemic (for example, anaphylaxis) including #17 #8 AND #16
time to onset (in minutes) of systemic reactions. We will combine these terms with the highly sensitive search strat-
egy designed by The Cochrane Collaboration for identifying ran-
domised controlled trials and controlled clinical trials in MED-
Secondary outcome measures LINE, and with adapted versions of this filter in EMBASE and
We will evaluate experimental outcomes, such as skin reactivity, CINAHL.
in both the immediate phase (15 minutes) and late phase (6 to Strategies for all other databases will be modelled on the CEN-
24 hours), and levels of specific IgE and IgG antibodies. These TRAL version (Table 1).
are of secondary importance because their relationship to clinical We will scan reference lists of identified publications for additional
efficacy is yet to be adequately established. trials and trial authors will be contacted if necessary. We will also

Allergen injection immunotherapy for perennial allergic rhinitis (Protocol) 3


Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
perform a search for existing meta-analyses and non-Cochrane C - Unmet; trials in which blinding of investigators was clearly
systematic reviews and scan their reference lists for additional trials. not performed.
There will be no language, publication year or publication status Trials which fall into allocation concealment category C will be
restrictions on searching. excluded from the analysis and the remaining studies will be given
an overall score using the following criteria:
A - Low risk of bias, where all criteria were ’adequate’.
Data collection and analysis B - Medium risk of bias, where one or more criteria were ’unclear’
and the rest were ’adequate’.
C - High risk of bias, where one or more of the criteria were
Study selection ’unmet’.
Study quality will be used in a sensitivity analysis. Due to prior
Three independent authors will check titles and abstracts identi- familiarity with the content of most studies, authors’ names will
fied from the searches. All authors will obtain the full text of all not removed before assessment.
studies of possible relevance for assessment. The authors will de-
cide which trials fit the inclusion criteria and grade their method-
ological quality. Any disagreement will be resolved by discussion
between the authors. We will contact study authors for clarifica- Data extraction
tion where necessary. Each of the suitable reports will be read in detail by MC, VC and
MJ. We will abstract relevant details onto a standard extraction
sheet (which covers study type and methodology; number and de-
Quality assessment
scription of subjects; details of type, dosage and time schedule/du-
We will assess methodological quality using the Jadad criteria ( ration of the intervention; and type, timing and method of mea-
Jadad 1996) and the Cochrane approach to quality assessment, surement of outcomes). We will assess concealment of allocation
which is detailed in section six of the Cochrane Handbook for and blinding of study participants and investigators according to
Systematic Reviews of Interventions (Higgins 2006). the Cochrane Collaboration guidelines.
Assessment of methodological quality:

Concealment of allocation to the intervention or placebo Data analysis


arm of the trial We will extract outcome data from the studies selected for inclu-
A - Adequate; for example, centralised randomisation by a central sion and use RevMan 4.2.10 (RevMan 2003) for statistical anal-
office. ysis. We will analyse all continuous outcome data on efficacy (i.e.
B - Unclear; list or table or apparently adequate concealment but symptom scores, medication scores) but it is recognised that au-
no other information in trial. thors use a wide variety of scoring systems and scales for symp-
C - Unmet; alternation, days of the week, any allocation that is toms (most frequently a daily quantification of nasal, ocular and
potentially transparent. chest symptoms entered on a diary card and subsequently totalled
and averaged) and rescue medication use (typically a daily score
reflecting oral antihistamine tablet, eye drop and nasal spray use
Attrition bias entered on a diary card and subsequently totalled and averaged).
A - Adequate; trials where an intention-to-treat analysis is possible We will record adverse reactions either per person or per injection
and drop-out rate was less than 20% after one year in all groups. and as local or systemic reactions. We will grade systemic reactions
B - Unclear; trials where drop-out rate was more than 20% after according to time of onset (early within 30 minutes and late after
one year or large differences in drop-out rates between groups were 30 minutes) and severity of reaction. For assessing the severity
observed. of systemic reactions we will follow the grading system proposed
C - Unmet; no reporting on drop-out rates and intention-to-treat in the Position Paper of the European Academy of Allergology
analysis not possible. and Clinical Immunology on Immunotherapy (as below) (Malling
1993).
Grade 1: Non-specific reactions: reactions probably not IgE-me-
Detection bias diated; i.e. discomfort, headache, arthralgia, etc.
A - Adequate; trials in which blinding of investigators assessing Grade 2: Mild systemic reactions: mild rhinitis and/or asthma
outcomes was adequate. (peak expiratory flow rates (PEFR) over 60% of predicted or per-
B - Unclear; trials in which blinding of investigators was not ade- sonal best values) responding adequately to antihistamines or in-
quately described. haled B2-agonists.

Allergen injection immunotherapy for perennial allergic rhinitis (Protocol) 4


Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Grade 3: Non life-threatening systemic reactions: urticaria, an- 7 - GLOBAL IMPROVEMENT
gioedema or severe asthma (PEFR under 60% of predicted or per- 8 - RHINOCONJUNCTIVITIS QUALITY OF LIFE
sonal best values) responding well to treatment. 9 - ADVERSE EVENTS
Grade 4: Anaphylactic shock: rapidly evoked reaction of itching, 9.1 - LOCAL REACTION
flushing, erythema, bronchial obstruction, etc. requiring intensive 9.1.1 - Local reaction not requiring treatment
treatment. 9.1.2 - Local reaction requiring treatment
We will carry out two key analyses: 9..2 - SYSTEMIC REACTION
• An examination of the efficacy of immunotherapy during 9.2.1 - Early systemic reaction grade 2 (< 30 minutes)
the period of the treatment; 9.2.2 - Early systemic reaction grade 3 (< 30 minutes)
• An examination of the risks of serious adverse reactions due 9.2.3 - Early systemic reaction grade 4 (< 30 minutes)
to treatment. 9.2.4 - Late systemic reaction (> 30 minutes)
9.2.5 - Systemic reaction - severity and time of onset not specified
We will present quantitative analyses of outcomes on an intention- 10 - ADRENALINE USE
to-treat basis. We will perform meta-analysis, where appropriate, 11 - COST
using a random-effects model to obtain summary statistics for the 12 - SERUM ANTIBODY LEVELS
overall efficacy of subcutaneous immunotherapy. We plan to ex- 12.1 - Specific IgG
press categorical data as odds ratios or relative risks (with 95% 12.2 - Specific IgG-4
confidence intervals). For continuous data, the standardised mean 12.3 - Specific IgE
difference (SMD) will be calculated (with 95% confidence inter- 13 - SPECIFIC ALLERGEN CHALLENGES
vals). The standardised mean difference standardises the outcome 13.1 - Nasal challenge
for each individual study to the effect size found in terms of the 13.2 - Conjunctival challenge
standard deviation observed (in the study). Calculation of SMD is 13.3 - Skin challenge
generally the method used for pooling data from different scales. 13.4 - Bronchial challenge
We will perform chi-squared tests to assess heterogeneity between 14 - DEATHS
studies, with a P value < 0.05 indicating significant differences Where appropriate, we will perform additional analyses according
between studies. to subgroup.
The following subgroups of comparisons between active and We will describe the characteristics of the treatments and partici-
placebo treated subjects are proposed: pants with the highest and lowest relative risk of adverse reaction.
1 - SYMPTOM SCORES We will perform tests for heterogeneity and if it is found to be
2 - MEDICATION SCORES significant, we will seek possible explanations through examination
3 - SYMPTOM AND MEDICATION SCORES of study quality and type of immunotherapy.
4 - NASAL SYMPTOM SCORES We plan to assess for evidence of publication bias graphically using
5 - BRONCHIAL SYMPTOM SCORES funnel plots and statistically using Begg and Egger tests (Begg
6 - OCULAR SYMPTOM SCORES 1994; Egger 1997).

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Allergen injection immunotherapy for perennial allergic rhinitis (Protocol) 6


Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ADDITIONAL TABLES
Table 1. MEDLINE & EMBASE SEARCH STRATEGIES

MEDLINE (DataStar) EMBASE (DataStar)

1. RHINITIS.DE. 1. ALLERGIC-RHINITIS.DE.
2. RHINITIS-ALLERGIC-PERENNIAL.DE. 2. PERENNIAL-RHINITIS.DE.
3. (allerg$3 OR hypersensitiv$5) NEAR (rhiniti$1 OR 3. HOUSE-DUST-ALLERGY.DE.
rhinopath$5 OR nose OR nasal OR cat$1 OR fur OR hair$1 OR 4. RHINITIS.W..DE. OR NOSE-ALLERGY.DE.
dander OR dust$1 OR mite$1 OR dustmite$1 OR pet$1 OR 5. (allerg$3 OR hypersensitiv$5) NEAR (rhiniti$1 OR
dog$1 OR cockroach$2 OR mould$1 OR mold$1 OR peren- rhinopath$5 OR nose OR nasal OR cat$1 OR fur OR hair$1 OR
nial$2 OR persist$3 OR nonseasonal$2 OR respiratory) dander OR dust$1 OR mite$1 OR dustmite$1 OR pet$1 OR
4. 1 OR 2 OR 3 dog$1 OR cockroach$2 OR mould$1 OR mold$1 OR peren-
5. (seasonal$2 NEAR allerg$3 OR seasonal$2 NEAR rhinitis OR nial$2 OR persist$3 OR nonseasonal$2 OR respiratory)
pollinosis OR pollen$4 OR grass$2 NEAR allerg$3 OR hay ADJ 6. 1 OR 2 OR 3 OR 4 OR 5
fever OR hayfever).TI. 7. (seasonal$2 NEAR allerg$3 OR seasonal$2 NEAR rhinitis OR
6. 4 NOT 5 pollinosis OR pollen$4 OR grass$2 NEAR allerg$3 OR hay ADJ
7. (non ADJ seasonal$2 NEAR (allerg$3 OR rhiniti$1)).TI. fever OR hayfever).TI.
8. 6 OR 7 8. 6 NOT 7
9. DESENSITIZATION-IMMUNOLOGIC.DE. 9. (non ADJ seasonal$2 NEAR (allerg$3 OR rhiniti$1)).TI.
10. ALLERGENS-IM.DE. OR ALLERGENS-TU.DE. OR AL- 10. 8 OR 9
LERGENS-AD.DE. 11. DESENSITIZATION.DE.
11. IMMUNOTHERAPY.W..DE. 12. ALLERGEN-DT.DE. OR ALLERGEN-TH.DE.
12. DOSE-RESPONSE-RELATIONSHIP- 13. HOUSE-DUST-ALLERGEN-DT.DE. OR HOUSE-
IMMUNOLOGIC.DE. DUST-ALLERGEN-TH.DE.
13. (immunotherap$3 OR immunomodulat$3 OR immune 14. IMMUNOTHERAPY.W..DE.
NEAR therap$3 OR immunologic$5 NEAR respons$7 OR de- 15. (immunotherap$3 OR immunomodulat$3 OR immune
sensiti$7 OR hyposensiti$7 OR subcutaneous$2).TI,AB. NEAR therap$3 OR immunologic$5 NEAR respons$& OR de-
14. 9 OR 10 OR 11 OR 12 OR 13 sensiti$7 OR hyposensiti$7 OR subcutaneous$2).TI,AB.
15. 8 AND 14 16. 11 OR 12 OR 13 OR 14 OR 15
17. 10 AND 16

WHAT’S NEW

Date Event Description

5 November 2008 Amended Converted to new review format.

Allergen injection immunotherapy for perennial allergic rhinitis (Protocol) 7


Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CONTRIBUTIONS OF AUTHORS
MA Calderón: conceiving the review; lead author; searching for trials; quality assessment; design of data extraction form; data extraction;
data analysis; writing manuscript; input at all other stages of review; having primary responsibility for the study.
VA Carr: protocol development; searching for trials; quality assessment; design of data extraction form; data extraction; writing
manuscript; data analysis; input at all other stages of review.
M Jacobson: searching for trials; quality assessment; data extraction; data analysis; input at all other stages of review.
A Sheikh: supervision of review process; writing manuscript; contribution to the discussion of results; input at all other stages of review.
SR Durham: supervision of review process; contribution to the discussion of results; input at all other stages of review.

DECLARATIONS OF INTEREST
None known.

Allergen injection immunotherapy for perennial allergic rhinitis (Protocol) 8


Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.