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
of allergy, supported by a diagnostic test to confirm an IgE medi-
ated cause. IgE mediated conditions are usually confirmed by skin
prick tests (SPT) or by measuring the specific IgE in the serum
(radio-allergosorbant or RAST test) in clinical practice. During
skin prick tests a small droplet of an allergen extract is placed on
the skin, usually the extensor surface of the forearm. The skin is
then pricked through the droplet with a specially designed lancet,
introducing a small amount of the extract beneath the skin. Com-
mon aero-allergen extracts are usually included and also positive
and negative controls to ensure quality and reliability. If specific
IgE is present a small wheal appears in the skin, which is measured
after 15 minutes. There are other methods of allergy diagnosis,
many of which are employed during research studies and where
diagnosis is in doubt, or not possible using conventional methods.
These include intradermal or cutaneous testing and bronchial and
conjunctival provocation tests (Durham 2006).
The management of allergic rhinitis includes avoidance measures.
However, there is increasing evidence that these measures do not
have a significant effect on allergic rhinitis symptoms, particularly
in house dust mite allergy (Sheikh 2007; Terreehorst 2003). Phar-
macological management in both adults and children is based on a
combination of topical nasal corticosteroids and long-acting, non-
sedating antihistamines (Al-Sayyad 2007; Bousquet 2001).
For some patients, treatment with a combination of antihistamines
and topical nasal corticosteroids does not adequately control symp-
toms. One study, investigating symptom control in patients with
hay fever in the United Kingdom, found that 62% of sufferers
treated with combination treatment still experienced troublesome
symptoms and described symptom control as only partial or poor
(White 1998). Many patients also state that allergy medications
can provoke unwanted side effects (Juniper 2005) and are con-
cerned about the effects of long-term use of pharmacotherapy, re-
sulting in patients being reluctant to use them (Malling 1993). For
this group of patients, where first line treatment is deemed to have
failed, allergen immunotherapy should be considered (Bousquet
1998).
Allergen immunotherapy can be delivered by subcutaneous injec-
tion, nasal, oral or sublingual routes. Subcutaneous injections are
the most common mode of delivery, although the results of a re-
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).
Allergen immunotherapy by injection (also known as hyposen-
sitisation or desensitisation) consists of a course of injections of
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
Allergen injection immunotherapy for perennial allergic rhinitis (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
and meta-analyses to be effective in reducing symptom scores and
medication use in patients with allergic rhinitis. (Calderon 2007;
Ross 2000).
The immunological mechanisms responsible for successful aller-
gen immunotherapy probably involve both the generation of tol-
erance toward the responsible allergen source and a shift in the
balance between the allergic Th2 and non-allergic Th1 allergic
phenotype (Robinson 2004).
It is important, as with all medical treatments, to consider any side
effects or adverse reactions that may occur. Side effects from subcu-
taneous immunotherapy can be both local and systemic. Swelling
at injection sites is described in many patients. While this can be
troublesome, it is rarely severe. Systemic reactions vary in severity
and range from relatively mild symptoms such as rhinitis to life
threatening symptoms involving severe asthma and anaphylaxis.
A four-point scale for classifying systemic reactions has been pro-
posed in the position paper of the European Academy of Allergol-
ogy and Clinical Immunology (Malling 1993). Grade 1 reactions
include mild, non-specific symptoms and anaphylaxis is given a
grade 4.
The risk of anaphylaxis is supported by a report published by
the British Committee for the Safety of Medicines (CSM 1986)
investigating the safety of subcutaneous immunotherapy, which
suggested that some limitations should be considered or enforced
when initiating treatment and treating patients. The report discov-
ered that 26 fatalities had occurred in the United Kingdom since
1957. It was after publication of this report that it was decided
that use should be limited to specialist practitioners in designated
clinics with full resuscitation facilities and that patients should be
observed for up to one hour after treatment. It was also recom-
mended that the treatment should not be administered to patients
with asthma, to people receiving treatment with beta-blocker ther-
apy or to those suffering from significant concurrent illness.
A recent Cochrane systematic review and meta-analysis (Calderon
2007) has shown that specific allergen injection immunotherapy
in suitably selected patients with seasonal allergic rhinitis results
in a significant reduction in symptom scores and medication use.
This review aims to evaluate the safety and efficacy of injection
immunotherapy for the treatment of perennial allergic rhinitis.
OBJECTIVES
To evaluate the effectiveness and safety of injection immunother-
apy in treating perennial allergic rhinitis.
METHODS
2
Criteria for considering studies for this review
Types of studies
Randomised, double blind, placebo controlled trials.
Types of participants
Patients suffering from perennial allergic rhinitis due to house dust
mite allergy, pet dander allergy, mould allergy or any combination.
Children and adults will be included. Allergy must be proven using
an objective test such as a skin prick test or specific IgE test (such
as the radioallergosorbant test (RAST)) or both.
Types of interventions
Multiple (defined as being three or more) injections of high-dose
immunotherapy with standardised single allergen extracts com-
pared with placebo treatment. High-dose immunotherapy will be
defined as being when the maintenance dose contains more than
5 micrograms of major allergen per millilitre.
Types of outcome measures
Primary outcome measures
1. Symptoms
• Symptom scores - typically collected using symptom diaries
• Daily patient-completed visual analogue scores
Preference will be given to formally validated symptom scores
wherever possible.
2. Clinical
• Medication use
• Rhinoconjunctivitis quality of life
• Adverse reactions: local (including swelling or itching to
injection site) and systemic (for example, anaphylaxis) including
time to onset (in minutes) of systemic reactions.
Secondary outcome measures
We will evaluate experimental outcomes, such as skin reactivity,
in both the immediate phase (15 minutes) and late phase (6 to
24 hours), and levels of specific IgE and IgG antibodies. These
are of secondary importance because their relationship to clinical
efficacy is yet to be adequately established.
Allergen injection immunotherapy for perennial allergic rhinitis (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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-
trolled Trials (CENTRAL) (The Cochrane Library, current is-
sue), MEDLINE (1950 onwards), EMBASE (1974 onwards),
CINAHL (1982 onwards), AMED (1985 onwards), LILACS,
KoreaMed, IndMed, PakMediNet, ZETOC, Cambridge Scien-
tific Abstracts (Conference Proceedings Database), ISI Proceed-
ings (Web of Science), IMEMR (Index Medicus for WHO East-
ern Mediterranean Region), IMSEAR (Index Medicus for WHO
South-East Asian Region), NRR (the National Research Register),
UKCRN (the UK Clinical Research Network Portfolio Database),
ICTRP (the World Health Organization International Clinical
Trials Registry Platform), ReFeR (the Research Findings Register)
and mRCT (the metaRegister of Controlled Trials).
The Cochrane Central Register of Controlled Trials (CENTRAL)
will be searched using the terms:
#1 RHINITIS single term (MeSH)
#2 RHINITIS ALLERGIC PERENNIAL single term (MeSH)
#3 (allerg* OR hypersensitiv*) NEAR (rhiniti* OR rhinopath* OR
nose OR nasal OR cat* OR fur OR hair* OR dander OR dust* OR
mite* OR pet* OR dog* OR cockroach* OR mould* OR mold*
OR perennial* OR persist* OR nonseasonal* OR respiratory)
#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
#6 #4 NOT #5
#7 (non NEXT seasonal* NEAR (allerg* OR rhiniti*)):ti
#8 #6 OR #7
#9 DESENSITIZATION, IMMUNOLOGIC single term
(MeSH)
#10 ALLERGENS [im] single term (MeSH)
#11 ALLERGENS [tu] single term (MeSH)
#12 ALLERGENS [ad] single term MeSH)
#13 IMMUNOTHERAPY single term (MeSH)
#14 DOSE RESPONSE RELATIONSHIP, IMMUNOLOGIC
single term (MeSH)
#15 immunotherap* OR immunomodulat* OR immune NEAR
therap* OR immunologic* NEAR respons* OR desensiti* OR
hyposensiti* OR subcutaneous*
#16 #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15
#17 #8 AND #16
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-
LINE, and with adapted versions of this filter in EMBASE and
CINAHL.
Strategies for all other databases will be modelled on the CEN-
TRAL version (Table 1).
We will scan reference lists of identified publications for additional
trials and trial authors will be contacted if necessary. We will also
3
perform a search for existing meta-analyses and non-Cochrane
systematic reviews and scan their reference lists for additional trials.
There will be no language, publication year or publication status
restrictions on searching.
Data collection and analysis
Study selection
Three independent authors will check titles and abstracts identi-
fied from the searches. All authors will obtain the full text of all
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-
tion where necessary.
Quality assessment
We will assess methodological quality using the Jadad criteria (
Jadad 1996) and the Cochrane approach to quality assessment,
which is detailed in section six of the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2006).
Assessment of methodological quality:
Concealment of allocation to the intervention or placebo
arm of the trial
A - Adequate; for example, centralised randomisation by a central
office.
B - Unclear; list or table or apparently adequate concealment but
no other information in trial.
C - Unmet; alternation, days of the week, any allocation that is
potentially transparent.
Attrition bias
A - Adequate; trials where an intention-to-treat analysis is possible
and drop-out rate was less than 20% after one year in all groups.
B - Unclear; trials where drop-out rate was more than 20% after
one year or large differences in drop-out rates between groups were
observed.
C - Unmet; no reporting on drop-out rates and intention-to-treat
analysis not possible.
Detection bias
A - Adequate; trials in which blinding of investigators assessing
outcomes was adequate.
B - Unclear; trials in which blinding of investigators was not ade-
quately described.
Allergen injection immunotherapy for perennial allergic rhinitis (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
C - Unmet; trials in which blinding of investigators was clearly
not performed.
Trials which fall into allocation concealment category C will be
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’.
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
’unmet’.
Study quality will be used in a sensitivity analysis. Due to prior
familiarity with the content of most studies, authors’ names will
not removed before assessment.
Data extraction
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-
scription of subjects; details of type, dosage and time schedule/du-
ration of the intervention; and type, timing and method of mea-
surement of outcomes). We will assess concealment of allocation
and blinding of study participants and investigators according to
the Cochrane Collaboration guidelines.
Data analysis
We will extract outcome data from the studies selected for inclu-
sion and use RevMan 4.2.10 (RevMan 2003) for statistical anal-
ysis. We will analyse all continuous outcome data on efficacy (i.e.
symptom scores, medication scores) but it is recognised that au-
thors use a wide variety of scoring systems and scales for symp-
toms (most frequently a daily quantification of nasal, ocular and
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
entered on a diary card and subsequently totalled and averaged).
We will record adverse reactions either per person or per injection
and as local or systemic reactions. We will grade systemic reactions
according to time of onset (early within 30 minutes and late after
30 minutes) and severity of reaction. For assessing the severity
of systemic reactions we will follow the grading system proposed
in the Position Paper of the European Academy of Allergology
and Clinical Immunology on Immunotherapy (as below) (Malling
1993).
Grade 1: Non-specific reactions: reactions probably not IgE-me-
diated; i.e. discomfort, headache, arthralgia, etc.
Grade 2: Mild systemic reactions: mild rhinitis and/or asthma
(peak expiratory flow rates (PEFR) over 60% of predicted or per-
sonal best values) responding adequately to antihistamines or in-
haled B2-agonists.
4
Grade 3: Non life-threatening systemic reactions: urticaria, an-
gioedema or severe asthma (PEFR under 60% of predicted or per-
sonal best values) responding well to treatment.
Grade 4: Anaphylactic shock: rapidly evoked reaction of itching,
flushing, erythema, bronchial obstruction, etc. requiring intensive
treatment.
We will carry out two key analyses:
• An examination of the efficacy of immunotherapy during
the period of the treatment;
• An examination of the risks of serious adverse reactions due
to treatment.
We will present quantitative analyses of outcomes on an intention-
to-treat basis. We will perform meta-analysis, where appropriate,
using a random-effects model to obtain summary statistics for the
overall efficacy of subcutaneous immunotherapy. We plan to ex-
press categorical data as odds ratios or relative risks (with 95%
confidence intervals). For continuous data, the standardised mean
difference (SMD) will be calculated (with 95% confidence inter-
vals). The standardised mean difference standardises the outcome
for each individual study to the effect size found in terms of the
standard deviation observed (in the study). Calculation of SMD is
generally the method used for pooling data from different scales.
We will perform chi-squared tests to assess heterogeneity between
studies, with a P value < 0.05 indicating significant differences
between studies.
The following subgroups of comparisons between active and
placebo treated subjects are proposed:
1 - SYMPTOM SCORES
2 - MEDICATION SCORES
3 - SYMPTOM AND MEDICATION SCORES
4 - NASAL SYMPTOM SCORES
5 - BRONCHIAL SYMPTOM SCORES
6 - OCULAR SYMPTOM SCORES
REFERENCES
Additional references
Al-Sayyad 2007
Al Sayyad JJ, Fedorowicz Z, Alhashimi D, Jamal A. Topical
nasal steroids for intermittent and persistent allergic rhinitis
in children. Cochrane Database of Systematic Reviews
2007, Issue 1. [Art. No.: CD003163. DOI: 10.1002/
14651858.CD003163.pub4]
Bauchau 2005
Bauchau V, Durham SR. Epidemiological characterisation
of the intermittent and persistent types of allergic rhinitis.
Allergy 2005;60(3):350–3.
Begg 1994
Begg CB, Mazumdar M. Operating characteristics of a rank
correlation test for publication bias. Biometrics 1994;50:
Allergen injection immunotherapy for perennial allergic rhinitis (Protocol)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
7 - GLOBAL IMPROVEMENT
8 - RHINOCONJUNCTIVITIS QUALITY OF LIFE
9 - ADVERSE EVENTS
9.1 - LOCAL REACTION
9.1.1 - Local reaction not requiring treatment
9.1.2 - Local reaction requiring treatment
9..2 - SYSTEMIC REACTION
9.2.1 - Early systemic reaction grade 2 (< 30 minutes)
9.2.2 - Early systemic reaction grade 3 (< 30 minutes)
9.2.3 - Early systemic reaction grade 4 (< 30 minutes)
9.2.4 - Late systemic reaction (> 30 minutes)
9.2.5 - Systemic reaction - severity and time of onset not specified
10 - ADRENALINE USE
11 - COST
12 - SERUM ANTIBODY LEVELS
12.1 - Specific IgG
12.2 - Specific IgG-4
12.3 - Specific IgE
13 - SPECIFIC ALLERGEN CHALLENGES
13.1 - Nasal challenge
13.2 - Conjunctival challenge
13.3 - Skin challenge
13.4 - Bronchial challenge
14 - DEATHS
Where appropriate, we will perform additional analyses according
to subgroup.
We will describe the characteristics of the treatments and partici-
pants with the highest and lowest relative risk of adverse reaction.
We will perform tests for heterogeneity and if it is found to be
significant, we will seek possible explanations through examination
of study quality and type of immunotherapy.
We plan to assess for evidence of publication bias graphically using
funnel plots and statistically using Begg and Egger tests (Begg
1994; Egger 1997).
1088–101.
Bousquet 1998
Bousquet J, Lockey R, Malling HJ. Allergen
immunotherapy: therapeutic vaccines for allergic diseases.
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Bousquet 2001
Bousquet J, van Cawenberge P, Khaltaev N. Allergic rhinitis
and its impact on asthma. ARIA workshop report. Journal
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Calderon 2007
Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh
A, Durham SR. Allergen injection immunotherapy for
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DJM, Gavaghan DJ, et al. Assessing the quality of reports of
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Juniper EF, Stahl E, Doty RL, Simons FER, Allen DB,
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monitoring in allergic rhinitis. Journal of Allergy and
Clinical Immunology 2005;115((3 suppl 1)):S390–413.
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Lund VJ, Aaronsen D, Bousquet J, Dahl R, Davies RJ,
Durham SR, et al. International consensus report on the
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diagnosis and management of rhinitis. Allergy 1994;49
(Suppl 19):1–34.
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Ross RN, Nelson HS, Finegold I. Effectiveness of specific
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∗
Indicates the major publication for the study
6
ADDITIONAL TABLES
Table 1. MEDLINE & EMBASE SEARCH STRATEGIES

MEDLINE (DataStar) EMBASE (DataStar)

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