Long-term preventive effects of allergen specific immunotherapy: a

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Long-term preventive effects of allergen specific immunotherapy: a systematic review and
meta-analysis
Azevedo L; Cardoso P; Coelho J; Gonçalves A; Maranhas M; Oliveira A; Pereira E; Pereira J;
Silva V; Teixeira C; [email protected]
João Fonseca, MD, PhD; Class 19
BACKGROUND: Allergen specific immunotherapy (SIT) has long been investigated as a
treatment for airway diseases such as allergic rhinitis and asthma, decreasing its symptoms and the
need for medication. However, its long-term efficacy is less established namely on the prevention of
new sensitivities and on the evolution from rhinitis to asthma, although some studies have already
encouraged new investigations about this subject. However, there isn’t any synthesis of them, so it is
important to summarize the existing data. AIMS: To investigate if SIT has long-term preventive
effects after the treatment ceases. We investigated the development of new sensitivities and the
evolution from rhinitis to asthma. METHODS: The long-term effects of SIT on rhinitis and asthma
were evaluated through a systematic review with meta-analysis. We searched PUBMED database
using terms such as immunotherapy, asthma, rhinitis, desensitization or prevention. The articles
selected were based on the criteria defined: reporting a controlled study and having data on the
effects of SIT in allergic airway diseases after stopping the treatment. The included articles were
evaluated by two reviewers. Articles without a clear classification of the initial diagnosis of the
participants were excluded. Furthermore, methodological quality assessment of the included studies
was elaborated through the Delphi List. RESULTS: Seven studies were included. Three of them
demonstrated that SIT reduces the probability of progression from rhinitis to asthma, even long after
the treatment ended. Two studies concluded that SIT is efficient on the prevention of new
sensitizations, after the treatment ceased. Only one study was considered of high quality. Regarding
the development of asthma symptoms we obtained an odds ratio of 0.36 [0.21, 0.62] (p=0.0002) and
regarding the appearance of new sensitivities the valour was 0.15 [0.07, 0.32]
(p<0.00001).
CONCLUSIONS: Despite the limited number of studies, this systematic review with meta-analysis
showed that SIT seems to prevent the development of asthma symptoms and the onset of new
sensitizations in patients with allergic rhinitis, even long after the treatment ended.
KEYWORDS: immunotherapy [Mesh]; asthma [Mesh]; rhinitis [Mesh]; desensitization,
immunologic [Mesh]; prevention [Mesh]
INTRODUCTION
During the last decades the number of people suffering from allergic diseases and asthma has
increased considerably.1
Today these diseases are very frequent; 2.7 million children in the United States suffer from
asthma and over a hundred million people suffer from asthma, allergy and chronic obstructive
pulmonary disease in Europe.2
An allergy, which may also be designated as hypersensitivity, is a disorder of the immune
system which appears in response to a substance (pollen, dust mites, mold spores, etc), usually
proteic, that isn’t harmful for the non sensitized people. People who suffer from allergies have a high
amount of a substance, Immunglobin E, in their blood.
Sensitivity is a term which designates a body reaction to a substance without the intervention
of Immunglobin E. When a person suffers from a sensitivity only parts of the immune system
intervene.
Rhinitis is frequently an allergic disease which consists of an inflammation of the mucous
membrane of the nose due to allergens, bacteria or irritant viruses. The consequence of this
inflammation is the formation of an excessive quantity of mucous, causing runny nose, nasal
congestion and post-nasal drip, which means, it causes the obstruction of the airways.
Asthma is often an allergic disease, too. It is characterized by airway obstruction and variable
inflammation. Clinically, asthma frequently causes breathing difficulties.
Allergen specific immunotherapy (SIT) is a desensitization method used to treat allergic
diseases. It reduces or even eliminates an organism’s negative reaction caused by a substance that,
in this case, is an allergen. Desensitization “teaches” the immune system to tolerate allergic triggers.
To find a solution for airway diseases like asthma and rhinitis, SIT has been developed. This
kind of treatment consists in the repeated administration of a specific allergen reducing the response
of the immune system and protecting against the allergic symptoms and inflammatory reactions
which are associated to natural exposure to the allergen in sensitive people. 3 Through the
introduction of small but increasing amounts of allergen at regular intervals, the way the immune
system of people who are being treated with SIT reacts will be altered. This means that SIT increases
the organism’s tolerance to a specific allergen.
There are two kinds of allergic SIT: sublingual (SLIT) and subcutaneous (SCIT).
SCIT consists of a subcutaneous injection of an extract of the allergen in solution. 4,5 On the
other hand, SLIT is a more recent form of administration and consists in the use of an allergen
solution under the tongue.
A systematic review concluded that SIT is efficient in the treatment of allergic rhinitis and
asthma.6 During the treatment, the observed results are the improvement in symptom control and a
reduction of the medication needs, which means that patients who have been treated with SIT are
less likely to require medication in comparison with patients who hadn’t taken SIT.
3,6,7,8
Nowadays, many authors support the idea that allergen SIT may be the only treatment for
diseases like asthma and rhinitis with long term efficacy.6
Some studies have suggested that SIT may also prevent the development of new sensitivities
and the reduction of the risk of developing asthma in patients with allergic rhinitis.8
The long term efficacy has been tested in few studies whose results show that adult patients
who suffered from rhinitis and received SIT during three years didn't develop asthma in the next six
years.9 However, there is no control group to compare with.
In a recent published article the SIT’s efficacy in the prevention of asthma is justified with a
reference to just one study which concluded that in two different populations of children suffering from
rhinitis – the one that received SIT and the placebo–treated children – there were significant
differences. While in the children that received SIT only 28% developed asthma, in the children that
weren’t treated with SIT 78% developed this airway disease.10 Another study concluded that in a
population of twenty two children who received SIT, 45% (10 out of 22) didn’t develop new
sensitivities while in the control group all of them developed new sensitivities. 11
In figure 1 the current knowledge about the effects of SIT is summarized.
SIT group
Patients with
airways allergic
diseases
Progression from rhinitis to
asthma ??
Control group
Follow-up
period
New allergic sensitivities ??
During the study
End of
the
intervention
-
End of
Follow-up
Decrease symptoms;
Decrease medication.
Figure 1 – Graphic contextualising the problem of this systematic review and meta-analysis.
In spite of these promising results, there are no studies summarizing the long-term effects of
SIT after the treatment ceases. It is well re-established that SIT decreases symptoms and medication
needs compared to placebo. However the long-term effects, namely the prevention of new allergic
sensitivities and the decrease in the risk of developing asthma, have been less studied and there is a
need to.
Data suggests that SIT may prevent the evolution from rhinitis to asthma and the appearance
of new sensitivities. Therefore we will do a systematic review to investigate this hypothesis, in order
to answer the question "Does allergen specific immunotherapy (SIT) have long-term preventive
effects in patients with allergic diseases?”.
-
Aims:
To investigate if SIT has long-term preventive effects after the treatment ceases. We
investigated the development of new sensitivities and the evolution from rhinitis to asthma.
PARTICIPANTS AND METHODS
The studies of interest were those reporting controlled trials on SIT treatment of allergen
rhinitis or asthma that provide information about the follow-up period.
Criteria selection
The inclusion criteria are:
-
Articles which refer to patients with allergic rhinitis or asthma treated with SIT;
-
Studies with, at least, one year of follow-up after the treatment ceases;
-
Articles reporting original data on the effects of immunotherapy on the:
-
•
progression from rhinitis to asthma ;
•
appearance of new allergic sensitivities;
Controlled studies.
The exclusion criteria are:
-
Studies that combine SIT with other types of treatment or medication;
-
Studies without a rigorous definition about the existence or not of asthma in the patients, at the
beginning of the treatment;
-
Articles in other language than the English.
Search Strategy
To make our systematic review we searched PUBMED database using the search terms
("Immunotherapy"[MeSH Terms] OR "Immunotherapy"[All Fields] OR ("desensitization,
immunologic"[MeSH Terms] OR "desensitization"[All Fields]) AND (("asthma"[MeSH Terms] OR
"asthm*"[All Fields]) OR ("rhinitis"[MeSH Terms] AND "rhinitis"[All Fields]) OR ("airway diseases"[All
Fields])) AND sensitive clinical query from PUBMED.
Furthermore, we searched for the references of the included studies and consulted the review
articles that have already been published about topics related to SIT. 6,12,13
Data Collection Methods
The articles found with the defined search terms were submitted to an evaluation by two
reviewers. When there wasn’t an agreement between them a third reviewer intervened, debating with
the other two in order to get an agreement between them. During this phase only titles and abstracts
were analysed (Figure 3). This analysis followed the selection criteria previously defined. When there
wasn’t sufficient information on the title or on the abstract, the article proceeded to the next phase.
The articles which didn’t accomplish the criteria were excluded and the reasons for that
exclusion were registered.
After this screening phase we proceeded with the inclusion phase. Here, the full text of the
potential included articles were searched and reviewed again by, at least, two reviewers following,
again, the selection criteria.
The excluded articles at this point of the work also had a registry of the reasons for that
exclusion.
Finally, we searched for the references of included articles and review articles on this subject.
At the end of this phase we had a list of the included articles.
Items extracted from each article were:

Study identification: author, year, country

Type of study;

Study’s objective;

Participants: number, age (children or adults), sex, health condition

Interventions: use of SLIT or SCIT, type of allergen administrated

Variables analysed: progression from rhinitis to asthma in patients treated with SIT and
in group control, severity of the symptoms (if developed), development of new
sensitivities in both patient groups, type of sensitivity developed (if developed),
behaviour’s differences in both groups;

Type of treatment;

Treatment duration;

Follow-up duration;

Control or placebo group;

Time: seasonal, not-seasonal, co-seasonal;

Results: development or not of asthma’s symptoms in patients with rhinitis that didn’t
have asthma at the beginning of the study; appearance or not of new allergic
sensitivities; development of other kinds of symptoms.
The methods used for data collection were similar to the recommendations for this type of
studies.15, 16, 17 The instrument for data collection that was used consists of a form that has been filled
with information extracted from the included articles.
Software Review Manager 4.2 Version and SPSS Software were used to process the data.
Variables description
The dependent variables studied were the non evolution from rhinitis to asthma and the
prevention of new sensitivities. We analysed if the patients, one year at least after the treatment with
SIT ceases, developed or not asthma symptoms or new sensitivities. The proportion of these
variables is expressed in odds ratio and intervals of confidence (95%).
The independent variables studied are the sex, age group and health condition of the
participants, the type of treatment administrated, the duration of treatment and follow-up, the
existence of a control or placebo group and the time of the administration (not-seasonal, co-seasonal
or
seasonal).
Methodological quality assessment
Two reviewers independently assessed the methodological quality using the Delphi list (Table
1).18
Each item (D1-D11) was scored as yes (=1), no (=0) or unclear (=0). The overall
methodological quality of a trial was computed by counting the number of positive scores, with equal
weights applied on all items. The trials with a score >/= 6 (range 0-11) were considered of high
quality.
Number
of
the item
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
Description of the item
Was a method of randomization performed?
Was the treatment allocation concealed?
Were the groups similar at baseline regarding the most important prognostic indicators?
Were both inclusion and exclusion criteria specified?
Was the outcome assessor blinded?
Was the care provider blinded?
Was the patient blinded?
Were point estimates and measures of variability presented for the primary outcome
measures?
Did the analysis include an intention-to-treat analysis?
Was the withdrawal/drop-out rate <20% of the total study population?
Was the withdrawal/drop-out rate unlikely to cause bias?
Table 1 – Items of the Delphi-list for the assessment of the methodological quality of the articles.
Statistical Analysis
The proportion of patients who developed new sensitivities and symptoms of asthma in the
intervention and in control groups were expressed through the calculation of odds ratio (OR), in order
to analyse the relation between the exposure and the outcome. Intervals of confidence were also
calculated. Moreover, tests of heterogeneity (Chi-Squared) were applied in order to evaluate the
validity of generalizations. Forest plot graphics were elaborated in order to summarize the data and to
explore the heterogeneity. The software used for this statistical analysis was Review Manager 4.2
Version. We also used SPSS for the descriptive statistics proportion (Bar Graphics).
RESULTS
Identification and selection of the literature
The search strategy resulted in 531 titles and abstracts. 125 were immediately considered
unsuitable for inclusion because they were review articles. So, 406 titles and abstracts were
analysed. After this analysis, 392 papers were excluded mainly because they didn’t have a follow-up
period or weren’t controlled studies. 14 full texts were obtained and analysed according to the criteria
selection. 10 of these 14 papers were excluded because they didn’t meet the minimum period of
follow-up that we defined (n= 9) and they didn’t refer to patients suffering from asthma and/or rhinitis
treated with SIT (n=1). Three trials were included after consulting the review papers on this subject.
Finally, 527 articles were excluded and 7 studies were included on the systematic review and
meta-analysis.
531 references identified
electronically
125 excluded - review articles
392 excluded based on title/abstract
14 electronically screened for
detailed evaluation
-
10 reports excluded
9 without one year, at least, of follow-up
1 not relative to patients suffering from asthma
and/or rhinitis
3 articles included after consulting the review papers
on this subject
4 reports included
7 studies included on the systematic review
Figure 2 - Flow diagram for the process for inclusion in the systematic review.
Description of the included articles
The included articles were analyzed according to the items already defined.
In
Annex
I
tables
summarizing
the
information
obtained
are
presented.
The participants were children in four studies and adults in three.
While in two of them
19, 20
the participants only had rhinoconjunctivitis, in other four the
participants had rhinitis and/or asthma.
In relation to the type of treatment administrated, two of the studies
19, 20
used SCIT with the
same allergen extracts (Phleum pratense and Betula verrucosa), another22 used SLIT while three of
them didn’t specify the type of SIT administrated.
Three studies administrated grass pollen allergen extracts while in the others the type of
allergen wasn’t reported.
Six studies had in common the period of treatment duration – 3 years, while in another
22
the
treatment lasted 4 to 5 years. In relation to the follow – up period, it was 3, 5, 8, 10 to 12 years.
In two studies
19, 20
SIT was administrated out of the season. In another study the treatment
was co-seasonal and in another it was seasonal. In two articles this information wasn’t referred.
Two included articles23, 24 are relative to the same study but with different follow-up periods.
Methodological quality assessment
The total Delphi’s values were similar, ranging from 4 to 6 out of 11. However one trial21
presented high quality, while the other six were considered of low quality (Table 2).
The description of “treatment allocation” (D2) and the “blinding of the care provider/patient”
(D6/D7) was insufficient in most trials, resulting in a low score of these items.
Article
D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 Total Delphi*
L. Jacobsen, et al.2007
1 0 1 0 1 0 0 1 1
0
0
5
B. Niggemann, et
al.2006
1 0 1 0 1 0 0 1 1
0
0
5
Pajno GB, et al.2001
0 0 1 1 0 0 0 1 1
1
1
6
Di Rienzo V, et al.2003
0 0 1 0 0 0 0 1 1
1
1
5
Eng, PA, et al. 2006
0 0 1 0 0 0 0 1 1
1
1
5
Eng, PA, et al. 2002
0 0 1 0 0 0 0 1 1
1
1
5
Durham SR., et al.1999
0 0 1 1 0 0 0 1 1
0
0
4
* Total Delphi (range 0-11): total score >/= 6 = high quality; <6 = low quality
Table 2 – Results of the methodological quality assessment.
Data extraction and analysis
The studies that analysed the progression from rhinitis to asthma concluded that during the
follow – up period, the number of patients who developed asthma symptoms were less in the SIT
group than in the control group (Table 3).
Development of new
sensitivities
Development of
asthma symptoms
Study
Pajno GB, et al. 2002
Eng PA, et al. 2002
Eng PA, et al. 2006
Di Rienzo V, et al. 2003
L. Jacobsen, et al. 2007
B. Niggemann, et al. 2006
SIT Group
25%
61%
0%
9%
25%
20%
Control Group
67%
100%
0%
96%
45%
43%
Table 3 – Results obtained by the included studies.
One study 19 obtained as a secondary outcome the development of new sensitizations. 57% of
the children who developed asthma also developed a new sensitization, while in the group of children
who didn’t develop asthma the percentage of children with new sensitizations was 50%. In this study,
16 out of 64 (25%) patients in SIT group developed asthma symptons, in comparison with 24 out of
53 (45%) in control group (OR=0.40 [0.18, 0.88]).
Niggemann, B, et al. 2006
20
concluded that 20% (15 out of 75) of the patients in SIT group
evolved from rhinitis to asthma while in the control group this percentage was 43% (29 out of 67).
The odds ratio of this study was 0.33 [0.16, 0.69].
The Di Rienzo V, et al. 2003 study
22
concluded that 9% of the patients of SLIT group
developed asthma, in comparison with 96% of the control group (OR=0.00 [0.00, 0.04]). It also
verified an increase of the number of patients with multiple sensitizations in SLIT group, in
comparison with the control group.
One study21 that analysed the development of new sensitizations concluded that 25% of the
children in SIT group show, at least, a new sensitization, while in the control group the percentage of
children who developed new sensitizations was 67% (OR=0.16 [0.07, 0.36]).
The Eng PA, et al. 2002 study
24
also analysed the appearance of new sensitizations. In this
trial, 61% (8 out of 13) of the SIT patients developed a new sensitivity, while in the control group this
percentage was 100% (10 out of 10). In this study the odds ratio was 0.07 [0.00, 1.53].
The Eng PA, et al. 2006 study
23
analysed both the development of new sensitivities and the
prevalence of asthma. It observed that the prevalence of sensitizations was 90% in the control group,
in comparison with 67% in the SIT group. They concluded, in comparison to a previous observation
that had been made six years before, that no patients (control or SIT group) developed new
sensitizations in that period.
Stephen R. Durham, et al. 1999
25
verified a decrease in the late skin response to allergen
challenge, after the discontinuation of SIT. This paper wasn’t referring any numbers or percentages.
Development of new sensitivities
Progression from rhinitis to asthma
2 studies: SIT is preventive
3 studies: SIT is preventive
Figure 3 – Diagram summarizing the results obtained in the systematic review.
Figure 3 - Meta-analysis of development of asthma symptoms: odds ratio (OR) with 95% confidence
interval (CI) for each study and all studies combined (include test for heterogeneity).
In this meta-analysis we didn’t include Di Rienzo V, et al. 2003 study 22, once it is impossible to
calculate the odds ratio valor through the results this study presents.
The odds ratio in favour of the treatment was 0.36 with 95% CI ranging from 0.21 to 0.62
(p=0.0002). There was a non significant homogeneity (Chi2 = 0.14, p = 0.71, I2 = 0%) among these
studies.
Figure 4 - Meta-analysis of development of new sensitivities: odds ratio (OR) with 95% confidence
interval (CI) for each study and all studies combined (include test for heterogeneity).
In this meta-analysis we didn’t include the Eng, PA, et al. 2006
continuation of the Eng, PA. 2002
24
23
study once it is a
study.
The odds ratio in favour of the treatment was 0.15 with 95% CI ranging from 0.07 to 0.32
(p<0.00001). There was a non significant homogeneity (Chi2 = 0.25, p = 0.61, I2 = 0%) among these
studies.
DISCUSSION
The results that we obtained suggest that this kind of treatment is efficient not only during its
administration but also after the treatment ceases. The majority of the included studies as well as the
results of the meta-analysis indicate that patients suffering from asthma and/or rhinitis that have been
submitted to SIT are less exposed to the appearance of new sensitivities after its end in comparison
with patients who didn’t take it. Besides, our analysis also proposes that people suffering from rhinitis
who have already been treated with SIT have less probability of developing asthma symptoms, in
comparison with people with the same disease but not submitted to this treatment.
One of the limitations of this systematic review with meta-analysis was the use of only one
database to search the articles. Although PUBMED is a wide database, some important studies that
could have been published only in other databases were missed out. However, the search of
references from studies and reviews improved the search. Another limitation of our work is the
publication bias, once the studies with negative results tend to be less published. So, there could be
studies contradicting the information that we obtained, however, they aren’t accepted to be published
once they are considered, by the editors, less significant in comparison with studies which obtain the
opposite results. Moreover, the number of studies is very limited.
Despite these limitations, the relevance of our work should be emphasized once there are few
systematic reviews and meta-analysis on this subject, that is, the number of articles which,
nowadays, focus on the long-term effects of SIT after the treatment ceases is small. On the other
hand, the number of studies reporting data on the effects of this type of treatment during its
administration is higher.
Future research is needed in order to obtain more information about the details of the influence
of SIT when the treatment stops and all the implications it could have in a long-term period.
Despite the limited number of studies, this systematic review with meta-analysis showed that
SIT seems to prevent the development of asthma symptoms and the onset of new sensitizations in
patients with allergic rhinitis, even long after the treatment ended.
ACKNOWLEDGEMENTS
Grateful thanks are extended to Altamiro Costa Pereira, MD, PhD for the constructive critics
and to João Fonseca, MD, PhD, for having supervised our work.
REFERENCES
1.
TePas EC, Umetsu DT. Immunotherapy of asthma and allergic diseases. Curr Opin
Pediatr. 2000 Dec; 12(6):574-8.
2.
Chin ES. Pediatrics, Reactive Airway Disease. eMedicine [Internet]. 2006 Nov [updated
2006 Nov 8; cited 2007Nov]. http://www.emedicine.com/emerg/TOPIC363.HTM
3.
James T. Li, MD, PhD; Richard F. Lockey, MD; I. Leonard Bernstein, MD; Allergen
immunotherapy: a practice parameter. Ann Allergy Asthma Immunol. 2003 Jan;
90(1):13-4.
4.
O'Hehir RE, Sandrini A, Anderson GP, Rolland JM. Sublingual allergen immunotherapy:
immunological mechanisms and prospects for refined vaccine preparation. Curr Med
Chem. 2007;14(21):2235-44.
5.
Greenberger PA, Ballow M, Casale TB, Platts-Mills TA, Sampson HA. Sublingual
immunotherapy and subcutaneous immunotherapy: Issues in the United States. J Allergy
Clin Immunol. 2007 Dec;120(6):1466-8.
6.
Cox L, Cohn JR. Duration of allergen immunotherapy in respiratory allergy: when is
enough, enough?. Ann Allergy Asthma Immunol. 2007 May; 98(5):416-26.
7.
Malling HJ. Allergen-specific immune therapy in the treatment of asthma. Ugeskr Laeger.
2000 Jan 24; 162(4):477-9.
8.
Passalacqua G, Durham SR. Allergic rhinitis and its impact on asthma update: allergen
immunotherapy. J Allergy Clin Immunol. 2007 Apr;119(4):881-91.
9.
Jacobsen L, Nuchel Petersen B, Wihl JAÊ , et al. Immunotherapy with partially purified
and standardized tree pollen extracts. IV: Results from long-term (6-year) follow-up.
Allergy. 1997; 52:914±920.
10. Johnstone DE, Dutton A. The value of hyposensitization therapy for bronchial asthma in
children: a 14-year study. Pediatrics. 1968; 42:793±802.
11. Des Roches A, Paradis L, Menardo JL, et al. Immunotherapy with a standardized
Dermatophagoides pteronyssinus extract. VI: Specific immunotherapy prevents the onset
of new sensitizations in children. J Allergy Clin Immunol. 1997; 99:450±453.
12. Calamita
Z,
immunotherapy
Saconato
in
H,
asthma:
Pela
AB,
Atallah
AN.
systematic
review
of
Efficacy
of
sublingual
randomized-clinical
trials
using the Cochrane Collaboration method. Allergy. 2006 Oct;61(10):1162-72.
13. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane
Database Syst Rev. 2003;(4):CD001186.
14. Calamita
Z,
immunotherapy
Saconato
in
H,
asthma:
Pela
AB,
Atallah
AN.
systematic
review
of
Efficacy
of
sublingual
randomized-clinical
trials
using the Cochrane Collaboration method. Allergy. 2006 Oct;61(10):1162-72.
15. Moher David, Cook DJ, Eastwood S, et al. Improving the quality of reports of metaanalyses of randomised controlled trials: the QUOROM statement. Onkologie. 2000
Dec;23(6):597-602.
16. Devillé WL, Buntinx F, Bouter LM, et al. Conducting systematic reviews of diagnostic
studies: didactic guidelines. BMC Med Res Methodol. 2002 Jul 3;2:9.
17. Pai M, McCulloch M, Gorman JD. Systematic reviews and meta-analyses: an illustrated,
step-by-step guide. Natl Med J India. 2004 Mar-Apr;17(2):86-95.
18.
Verhagen AP, De Vet HCW, De Bie RA, et al. The Delphi List: a criteria list of quality
assessment of randomized clinical trials for conducting systematic reviews developed by
Delphi consensus. J Clin Epidemiol. 1998 Dec;51(12):1235-41.
19. Jacobsen L, Niggemann B, Dreborg S, et al. Specific immunotherapy has long-term
preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study.
Allergy. 2007 Aug;62(8):943-8.
20.
Niggemann B, Jacobsen L, Dreborg S, et al. Five-year follow-up on the PAT study:
specific immunotherapy and long-term prevention of asthma in children. Allergy. 2006
Jul;61(7):855-9.
21.
Pajno GB, Barberio G, De Luca F, et al. Prevention of new sensitizations in asthmatic
children monosensitized to house dust mite by specific immunotherapy. A six-year followup study. Clin Exp Allergy. 2001 Sep;31(9):1392-7.
22. Di Rienzo V, Marcucci F, Puccinelli P, et al. Long-lasting effect of sublingual
immunotherapy in children with asthma due to house dust mite: a 10-year prospective
study. Clin Exp Allergy. 2003 Feb;33(2):206-10.
23. Eng PA, Borer-Reinhold M, Heijnen IA, et al. Twelve-year follow-up after discontinuation
of preseasonal grass pollen immunotherapy in childhood. Allergy. 2006 Feb;61(2):198201.
24. Eng PA, Reinhold M, Gnehm HP. Long-term efficacy of preseasonal grass pollen
immunotherapy in children. Allergy. 2002 Apr;57(4):306-12.
25. Durham SR, Walker SM, Varga EM, et al. Long-term clinical efficacy of grass-pollen
immunotherapy. N Engl J Med. 1999 Aug 12;341(7):468-75.
ANNEX I
Study identification:
Author
L.
Jacobsen
et al.
B.
Niggmenn,
et al.
Year
2007
2006
Country
Participants:
Type of
study
Study’s
objective
To investigate
if the
preventive
effect of
Denmark Prospective
developing
study
asthma
persisted 7
years after
termination of
SIT (at 10
year follow-up)
To investigate
the potential
long-term
preventive
effects on the
Prospective development
Germany
study
of asthma in
children with
seasonal
allergic
rhinoconjuncti
vitis 2 years
after
termination of
SIT(at 5 year
follow-up)
Number
Sex
147
Not
reporte
d
183
121males;
62female
s
Age
(children
or
adults)
Variables analysed
Health condition
rhinoconjunctivitis
16-25
years
11-20
years
Progression from
rhinitis to asthma in
patients treated with
SIT and in group
control
rhinoconjunctivitis Progression from
rhinitis to asthma in
patients treated with
SIT and in group
control
Eng, PA,
et al.
Di Rienzo
V, et al.
Pajno GB,
et al.
2006
2003
2001
Switzerla
nd
Italy
Italy
Prospectiv
e study
Clinical
Trial
Clinical
Trial
To investigate
whether there
is a prolonged
benefit 12
years
after SIT is
stopped
To evaluate
whether a
long-lasting
effect of SLIT
occurs, in a
prospective
parallel group
controlled
study.
To increase
the knowledge
of the ability of
SIT to prevent
the onset of
new
sensitizations
in
monosensitize
d subjects, so
far poorly
documented.
22
16
males;
6
female
s
Male:
31
60
Femal
e: 29
Male:
58
138
Femal
e: 80
20 -31
years
Rhinoconjunctiviti
s with or without
asthma;
sensitivity to
grass pollen
Skin
prick test (SPT)
reactivity to grass
pollen; development
of
new sensitizations;
prevalence of
seasonal asthma
due to
grass pollen allergy
Children
Mean
age: 8.5
years
Children
5-8
years
Allergic asthma/
rhinitis due to
mites
Intermittent
asthma with or
without rhinitis,
with single
sensitization to
mite allergen
-
The presence
and frequency
of asthma
Grading
severity of
asthma
The rate of asthma/
asthma+ rhinitis at
the beginning of the
trial and the
occurrence of new
sensitizations in
SIT-treated and
untreated children.
Eng, PA,
et al.
Durham
SR, et al.
2002
1999
Switzerla
nd
England
Prospectiv
e study
Clinical
Trial
Determine if
SIT with grass
pollen
allergoids in
childhood is
still effective
six years after
discontinuation
and if the
natural course
of the disease
can be
modified
by early
intervention
with SIT,
especially with
regard to
disease
progression
and onset of
new
sensitizations.
To examine
the effects of
the
discontinuation
of
immunotherap
y for three
years in the
28
Not
report
ed
Male:
29
47
Femal
e: 18
Children
5-16
years
Adults:
33-42
Severe hayfever
and IgEmediated
sensitivity to
seasonal
allergens only
(grass pollen with
or
without tree
pollen).
IgEmediated
seasonal allergic
rhinoconjunctivitis
with or
without seasonal
asthma
Seasonal allergic
rhinitis
Hayfever symptom
score, individual eye
nose and chest
symptoms score, the
appearance of new
sensitivities,
seasonal
rhinoconjunctivitis
(and pollen asthma
in addition to this).
Scores for seasonal
symptoms and the
use of rescue
medication. The
conjunctival
response and the
immediate and late
skin responses to
same group of
patients
Table 4 – Characteristics of the included studies.
allergen challenge.
Study
L. Jacobsen
et al.
Type of
treatment*
SCIT :
- allergen
extracts
of
grass pollen
(Phleum
pratense)
and/or
birch
pollen (Betula
verrucosa)
SCIT:
B.
- allergen
Niggmenn, et extracts
of
al.
grass pollen
(Phleum
pratense)
and/or
birch
pollen (Betula
verrucosa)
Treatment
duration*
Followup
duration
Time
Control (seasonal,
or
not
placebo seasonal,
group*
coseasonal)*
3 years
10 years
Control
group
Not
seasonal
3 years
5 years
Control
Group
Not
seasonal
Results
Before the beginning of SIT there were 117 patients
without asthma. After the 10 year period, the number
of patients who developed asthma among controls
was 24 of a total of 53 and in the actively treated
group 16 of a total of 64. The odds ratio was 2,5 (1,1
– 5,9). It has already been verified that 30% (18 of 61)
of the children who developed asthma during the 10year follow-up also developed a positive skin prick
test to house dust mites compared with 17% (15 of
86) of the children who did not develop asthma.
Furthermore, in the group of children who developed
asthma during the 10 year period there were 35 out of
61 (57%) who also developed a positive skin prick
test to one or more of the following allergens – house
dust mite, cat or dog allergen – in comparison with
50% (43 of 86) of the children who did not develop
asthma.
Of the 183 patients, 142 had no asthma at inclusion.
In SIT group it was verified that 20% (15 out of 75) of
the patients developed asthma (it was considered non
significant) while in control group the percentage of
people with asthma symptoms was 39% (29 out of
67) (P < 0.01), after 5 years. The odds ratio in favour
of the hypothesis that SIT can prevent the long-term
development of asthma was 2.68 (1.3 – 5.7, P <
0.05).
Eng, PA, et
al.
3 years
12 years
Control
group
Coseason
al
SIT
Di Rienzo V,
et al.
Pajno GB, et
al.
SLIT
4 to 5 years
10 years
Control
group
SIT
3 years
3 years
Control
group
3 years
Eng, PA, et
al.
SCIT :
-grass pollen
allergen
extracts
8 years
Control
group
Not
reported
Not
reported
Seasonal
There was a reduction in development of new
sensitizations after
SIT in the 12-year follow-up study
(P < 0.05). The prevalence of
sensitization to tree pollen was 90% in the controls
and
67% in the post-SIT group.
There was a tendency for lower asthma
prevalence in the post-SIT group, but without
reaching statistical significance (P ¼ 0.08).
In the SLIT group there was a significant difference
vs. baseline for the presence of asthma (P </= 0.01),
whereas no difference was observed in the control
group. The mean peak expiratory flow result was
significantly higher in the active group than in the
control group after 10 years. No change was seen as
far as new sensitizations were concerned. Specific
IgE showed a near-significant increase (baseline vs.
10 years, P = 0.06) only in the control group.
123 children completed the follow-up study. At the
end of the study, 52 out of 69 children (75.4%) in the
SIT Group showed no new sensitization, compared to
18 out of 54 children (33.3%) in the Control Group (P
< 0.0002). Parietaria, Gramineae and Olea were the
most common allergens responsible for the new
sensitization(s).
During the 13 week observation time scores for
overall hayfever symptoms and individual symptoms
for eyes, nose and chest remained lower in the group
with previous SIT. Only 23% of
patients with previous pollen-asthma who had
received SIT experienced pollenassociated
lower respiratory tract symptoms compared to 70% in
the control group. There was no significant difference
in the use of pharmacological
treatment during the pollen season except for asthma
medication. The average visual analog scale was
lower in the post-SIT group (P<0.05). Six years after
cessation of SIT the immediate skin response to
grass pollen remained
decreased compared to the reaction of the controls.
There was also a tendency for higher allergen
concentration to provoke a conjunctival response in
the post-SIT group but without reaching statistical
significance. Eight years after
commencement of SIT, 61% of the initially pollenmonosensitized children had
developed new sensitization to perennial allergens
compared to 100% in the
control group.
Durham SR,
et al.
SIT
3-4 years
3 years
Control
AND
Placebo
group
Not
reported
Scores for total hay fever symptoms, rescue
medication, and the visual
analogue scale for both the maintenance group and
the discontinuation group had no significant
differences in any of these scores between these two
groups throughout the three-year period.
Symptom and rescue-medication scores in both
groups were markedly lower than those in patients in
the control group.
* Relative to the clinical trial that is associated
Table 5 – Characteristics of the included articles.
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