The Laryngoscope

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Rhinological and Otological Society, Inc.

Systematic Review

Effectiveness of Subcutaneous Immunotherapy for Allergic

Rhinoconjunctivitis and Asthma: A Systematic Review

Nkiruka Erekosima, MD, MPH; Catalina Suarez-Cuervo, MD; Murugappan Ramanathan, MD;
Julia M. Kim, MD, MPH; Yohalakshmi Chelladurai, MBBS, MPH; Jodi B. Segal, MD, MPH;
Sandra Y. Lin, MD

Objectives/Hypothesis: To systematically review the effectiveness and safety of subcutaneous immunotherapy (SCIT)
for treatment of allergic rhinoconjunctivitis and asthma, using formulations currently approved in the United States.
Study Design: We searched the following databases up to May 21, 2012: MEDLINE, Embase, LILACS, and the Cochrane
Central Register of Controlled Trials.
Methods: We included randomized controlled trials published in English comparing SCIT to placebo, pharmacotherapy,
or other SCIT regimens that reported clinical outcomes of interest. Studies of adults or mixed age populations were included.
Studies were excluded if the diagnosis of allergy and/or asthma was not confirmed with objective testing. Paired reviewers
selected articles for inclusion and extracted data. We assessed the risk of bias for each study and graded the strength of evi-
dence for each outcome as high, moderate, or low.
Results: Sixty-one studies met our inclusion criteria. Majority of the studies (66%) evaluated single-allergen immunotherapy
regimens. The literature provides high-grade evidence that SCIT reduces asthma symptoms, asthma medication usage, rhinitis/rhi-
noconjunctivitis symptoms, conjunctivitis symptoms, and rhinitis/rhinoconjunctivitis disease-specific quality of life in comparison
to placebo or usual care. There is moderate evidence that SCIT decreases rhinitis/rhinoconjunctivitis medication usage. Respiratory
reactions were the most common systemic reaction. There were few reports of anaphylaxis; no deaths were reported.
Conclusions: Generally moderate to strong evidence supports the effectiveness of SCIT for treatment of allergic rhinitis
and asthma, particularly with single-allergen immunotherapy regimens. Adverse reactions to SCIT are common, but no deaths
were reported in the included studies.
Key Words: Allergy, rhinology.
Level of Evidence: 1a.
Laryngoscope, 124:616627, 2014

From the Division of Allergy and Clinical Immunology, Depart-

ment of Medicine (N.E.), Department of Medicine (C.S.-C., Y.C., J.B.S.),
Department of OtolaryngologyHead and Neck Surgery (M.R., S.Y.L.), and
Department of Pediatrics (J.M.K.), Johns Hopkins University School of
Medicine, Baltimore, Maryland, U.S.A
Editors Note: This Manuscript was accepted for publication June
14, 2013.
The authors have no other funding, financial relationships, or con-
flicts of interest to disclose.
S.Y.L. serves as a consultant for Wellpoint Consulting. This study
was funded by the Agency for Healthcare Research and Quality (AHRQ).
AHRQ staff participated in formulating the key questions and
reviewed planned methods and data analyses, as well as interim and
final evidence reports. They had no role in study selection, quality rat-
ings, or interpretation and synthesis of the evidence.
The authors of this article are responsible for its contents, includ-
ing any clinical or treatment recommendations. No statement in this
article should be construed as an official position of AHRQ or of the US
Department of Health and Human Services. This research was con-
ducted by the Johns Hopkins University Evidence-Based Practice Center
under contract to the AHRQ, Rockville, Maryland.
Send correspondence to Sandra Y. Lin, MD, 601 N. Caroline
Street, #6254, Baltimore, MD 21287. E-mail: slin30@jhmi.edu
DOI: 10.1002/lary.24295
INTRODUCTION
Allergic rhinitis affects 10% to 30% of adults in the
United States.1 Asthma affects 9% of the US population,
and approximately 62% of individuals with asthma have
atopy.2 Allergen immunotherapy is typically recom-
mended for patients whose allergic rhinoconjunctivitis
and asthma symptoms cannot be controlled by environ-
mental measures and pharmacotherapy or those who do
not tolerate or adhere to their medication regimens.3
Subcutaneous immunotherapy (SCIT), first intro-
duced by Noon in 1911 as a means of treating allergic
symptomatology,4 involves administering increasing
doses of an allergen-containing extract to suppress or
eliminate allergic symptoms through modulation of a
patients immune system. Recent approaches with modi-
fied and recombinant allergens, immunostimulatory
adjuvants, T-celltolerizing constructs, and improved
oral approaches have shown promise for treatment of
allergic respiratory disease. However, these are

Laryngoscope 124: March 2014 Erekosima et al.: Subcutaneous Immunotherapy Systematic Review
616
investigational and are not licensed for clinical use in
the United States.5 Other delivery routes such as sublin-
gual, intranasal, epicutaneous, intrabronchial, and intra-
lymphatic are also currently considered investigational
in the United States,5 although sublingual immunother-
apy is prescribed off-label by some practitioners.
In this study, we sought to review the evidence for
the effectiveness and safety of SCIT for treatment of
adults with allergic rhinitis/rhinoconjunctivitis and/or
asthma, focusing on SCIT formulations that are avail-
able in the United States. This review is part of an evi-
dence report commissioned by the US Agency for
Healthcare Research and Quality (AHRQ).
MATERIALS AND METHODS
We recruited technical experts for input on the research
questions and search strategy. We developed a protocol
and posted it online, following guidelines for systematic
review (http://effectivehealthcare.ahrq.gov/ehc/products/270/
665/SIT_Protocol_20110824.pdf). Additional methods details
are in the full AHRQ Evidence Report, which can be accessed
online at http://effectivehealthcare.ahrq.gov/search-for-guides-
reviews-and-reports/?pageaction5displayproduct&productID5
1427&ECem5130327.
Data Sources and Searches
We searched the following databases rigorously: MEDLINE
(from 1950 to May 21, 2012), Embase (from 1947 to May 21,
2012), Cochrane Central Register of Controlled Trials (to May 21,
2012), and LILACS (from 1982 to May 21 2012; Supplementary
Methods: Search Strategy). We also searched public registries of
clinical trials (www.clinicaltrials.gov) and requested Scientific
Information Packets from relevant pharmaceutical companies.
Study Selection
We reviewed titles and then abstracts to identify random-
ized controlled trials (RCTs) reporting on SCIT. We required
that the RCTs enrolled patients with allergic rhinoconjunctivitis
and/or allergic asthma due to aeroallergens, and that these
diagnoses were confirmed with objective testing. The trials
must have tested SCIT alone or in combination with usual care,
which included pharmacotherapy and environmental interven-
tions. We included trials if the comparators were placebo, other
SCIT regimens, or pharmacotherapy. For inclusion, the trials
must have reported symptoms, medication use, results of provo-
cation tests, quality of life, or harms of treatment. Studies were
excluded if they only tested SCIT formulations that are not cur-
rently available in the United States, or if the article was not
available in English. We also excluded studies that did not
clearly report the dose of allergen delivered.
Data Extraction and Quality Assessment
Outcomes of interest included symptom scores, medication
scores, combined symptom and medication scores, quality of
life, and safety or harms. Asthma outcomes were extracted only
if subjects in the study were diagnosed with asthma using
objective criteria, or according to established clinical guidelines.
For studies that recorded outcomes at multiple time
points, we used the outcome data from the final time point
reported. For studies assessing subjects during a single season,
Laryngoscope 124: March 2014 Erekosima et al.: Subcutaneous Immunotherapy Systematic Review
we extracted the outcomes at peak pollen seasons when
available.
Two reviewers independently assessed the risk of bias in
each article and came to consensus about the overall rating. We
used a modification of the Cochrane Collaboration Tool for
Assessing Risk of Bias from the Cochrane Handbook for Sys-
tematic Reviews of Interventions.6 Studies were categorized as
having a low, moderate, or high risk of bias.
Data Synthesis and Analysis
We summarized the studies by outcomes, by comparators,
and then by allergen. Given the substantial heterogeneity
between studies and the lack of reporting of measures of var-
iance, we did not quantitatively pool the data on efficacy. We
graded the quantity, quality, and consistency of the best avail-
able evidence by adapting an evidence grading scheme recom-
mended by the Guide for Conducting Comparative
Effectiveness Reviews.6,7 The magnitude of effect was classi-
fied according to the percentage difference in before to after
change comparing the SCIT group and comparator group;
<15% was defined as a weak difference, a 15% to 40% differ-
ence as moderate, and >40% as a strong effect. The body of
evidence for each primary outcome was graded as 1) high
grade, 2) moderate grade, 3) low grade, or 4) insufficient.6,7
The evidence grade reflects the likelihood that additional
research will change the conclusions about the intervention.
The following system was used to assign the evidence grade
for each outcome: high grade evidence required two or more
trials with low risk of bias, and at least one strong magnitude
of effect in the context of largely consistent overall evidence.
Moderate-grade evidence required one or more trials with low
risk of bias and strong magnitude of effect, or at least two tri-
als with medium risk of bias and strong magnitude of effect, or
one trial having low risk of bias with moderate magnitude of
effect plus one trial having medium risk of bias with strong
magnitude. Evidence was low grade if it did not meet any of
these categories. Insufficient evidence was assigned if there
were no relevant trials. The team reviewed and came to con-
sensus on the grades. The evidence regarding indirect outcome
measures (pulmonary function test results and provocation
tests) was not graded.
RESULTS
We identified 7,746 potentially relevant citations.
Sixty-one RCTs (12 asthma, 23 rhinitis/rhinoconjunctivi-
tis, and 26 combined asthma and rhinitis/rhinoconjunc-
tivitis studies) including 3,577 subjects met criteria for
inclusion (Fig. 1). Supplementary Appendix A describes
the characteristics of the individual studies.
Study and Population Characteristics
The studies were published between 1967 and
2012. Forty-four studies (72%) focused exclusively on
adults (aged 1872 years) and 17 (28%) included adults
and children (aged 756 years). Forty-four studies
(72%) were placebo-controlled (36 were designed as
SCIT vs. placebo; eight comparing different SCIT regi-
mens also included a placebo arm); 11 were SCIT ver-
sus SCIT; and one compared SCIT versus an untreated
control group. Only five studies were specifically
designed to compare SCIT versus pharmacotherapy.812
However, most studies (75%) allowed the use of medica-
tions, either routinely or as needed for symptom
617

control; others did not state whether medications were
allowed.
Forty studies used a single allergen for immuno-
therapy, whereas the remaining 21 studies used multiple
allergens. The majority (38 studies or 62%) evaluated
seasonal allergens including trees, grasses, weeds, and
seasonal molds; 23 studies (38%) evaluated perennial
allergens. Allergen doses varied across studies.
Seventeen studies (28%) had a low risk of bias. Thirty-
four studies (56%) were assessed as having a medium risk
of bias, and 10 studies (16%) had a high risk of bias.
Evidence for Effectiveness of SCIT
Table I summarizes the findings according to out-
comes. Six of the included studies were not graded
because all study arms received immunotherapy.1318
Asthma Outcomes
Asthma symptoms. Ten studies evaluated SCIT for
control of asthma symptoms, including 628 partici-
Laryngoscope 124: March 2014
618
Fig. 1. Literature search and selec-
tion of subcutaneous immunother-
apy studies. *Total may exceed
number in corresponding box, as
articles were excluded by two
reviewers at this level. **Other rea-
sons: control group is healthy popu-
lation, routes of administration not
included (e.g., oral, nasal, lymph
node), abandoned interventions, out-
comes not reported, no comparator
group, continued medical education
reports, editorials or reviews, studies
about mechanism of action, other
allergies (food, aspirin), study in ani-
mals or in vitro, less than six
patients per arm. RC 5 rhinoconjunc-
tivitis; RCT 5randomized controlled
trial; SCIT 5subcutaneous immuno-
therapy; SLIT 5 immunotherapy.
pants.1928 All used a single allergen, with dust mites
studied in six studies. Eighty percent were placebo-
controlled trials. Ninety percent of studies demonstrated
a greater improvement in the SCIT group than the com-
parator. The strength of evidence is high to support that
SCIT improves asthma symptom scores (Supplementary
Appendix B, Table 1).
Combined asthma plus rhinitis/rhinoconjunc-
tivitis symptoms. Five asthma studies including 175
participants reported combined asthma plus rhinocon-
junctivitis symptom scores.10,25,2931 Each study used a
different allergen; these included specific pollens,10,25,29
Alternaria,30 and cat allergen.31 Four were placebo-con-
trolled25,2931; one compared SCIT to pharmacotherapy.
All studies demonstrated greater improvement in the
SCIT groups than the comparator. The strength of evi-
dence is moderate to support that SCIT improves com-
bined asthma and rhinoconjunctivitis symptom scores
(Supplementary Appendix B, Table 2).
Asthma medication use. Eight studies, includ-
ing 592 subjects, reported asthma medication
Erekosima et al.: Subcutaneous Immunotherapy Systematic Review
 TABLE I.
Effectiveness of Subcutaneous Immunotherapy Evidence Summary Table.
Strength of Evi- No. of No. of Allergens Comparators Summary of Strength of
dence Domains Studies Participants (No. of Studies) (No. of Studies) Findings Grading Data Evidence

Outcomes in asthma studies

Asthma 10 628 Dust mite (6), Clado- SCIT vs. placebo (8), 9 of 10 studies dem- 4 studies with low RofB High
symptoms sporium (1), timothy vs. pharmacotherapy onstrated greater and 2 of these with
(1), ragweed (1), cat (1), vs. no SCIT (1) improvement in the strong magnitude; over-
(1) SCIT group than the all consistent
comparator.
Asthma plus 5 175 Parietaria (1), Alternaria SCIT vs. placebo (4) All SCIT groups con- 2 studies with low RofB, 1 Moderate

Laryngoscope 124: March 2014

rhinitis/rhino- (1), birch (1), timothy vs. pharmacotherapy sistently showed of which has moderate
conjunctivitis (1), cat (1) (1) greater improvement magnitude plus 1 study
symptoms than the with medium RofB and
comparators. strong magnitude; over-
all consistent
Asthma medi- 8 592 Dust mite (5), ragweed SCIT vs. placebo (6), 5 studies showed 2 studies with low RofB High
cation scores (1), Cladosporium vs. pharmacotherapy greater reduction in and 1 has strong mag-
(1), birch (1) (1), vs. no SCIT (1) medication use in nitude; overall
the SCIT group.2 consistent
studies did not
report direction of
change, and magni-
tude of effect could
not be calculated.
Asthma plus 3 123 Parietaria (1), birch (1), SCIT vs. placebo (2), All studies showed sig- 1 study with low RofB and Moderate
rhinitis/rhino- timothy (1) vs. pharmacotherapy nificant reduction in strong magnitude; over-
conjunctivitis (1) asthma plus rhino- all consistent
medication conjunctivitis medi-
scores cation use in the
SCIT group when
compared to
controls.
Asthma/ 4 111 Dust mite (1), Alterna- SCIT vs. placebo (3), All studies reported 1 study with high RofB Low
asthma plus ria (1), cat (1), Clado- vs. pharmacotherapy greater improvement and strong magnitude;
rhinitis symp- sporium (1) (1) in the SCIT group all other studies with
tommedica- than the comparator. insufficient data regard-
tion scores ing magnitude of effect;
overall consistent
Pulmonary 11 873 Dust mite (6), cat (2), SCIT vs. placebo (7), Variable and inconsis- Not graded Not graded
function test birch (2), ragweed vs. pharmacotherapy tent findings.
results (1) (2), vs. no SCIT (1),
SCIT cluster vs.
SCIT conventional
(1)
Specific aller- 11 353 Dust mite (6), cat (3), SCIT vs. placebo (10), All studies demon- Not graded Not graded
gen bronchial ragweed (1), birch SCIT cluster vs. strated significant
reactivity (1) SCIT conventional decreases in bron-
(1) chial reactivity favor-
ing the SCIT group
over the comparison
group.

619
Erekosima et al.: Subcutaneous Immunotherapy Systematic Review
 TABLE I.

620
(Continued)
Strength of Evi- No. of No. of Allergens Comparators Summary of Strength of
dence Domains Studies Participants (No. of Studies) (No. of Studies) Findings Grading Data Evidence

Nonspecific 13 568 Dust mite (6), cat (3), SCIT vs. placebo (10), Five studies demon- Not graded Not graded
bronchial birch (2), timothy (1), vs. pharmacotherapy strated significant
reactivity Alternaria (1) (2), SCIT cluster vs. decreases in bron-
SCIT conventional chial reactivity favor-
(1) ing the SCIT group
over the comparison
group.
Outcomes in rhinitis studies

Laryngoscope 124: March 2014

Rhinitis/rhino- 23 1,479 Timothy (4), dust mite SCIT vs. placebo (20), 20 studies showed 7 studies with low RofB High
conjunctivitis (4), ragweed (3), vs. pharmacotherapy greater improvement and 4 of these with
symptoms Parietaria (2), grass (2), vs. SCIT (5)all in symptoms in the strong magnitude; over-
mix (4), tree (2), with appropriate SCIT group than the all consistent
Alternaria (1), cat (1), control groups comparator18
multiple (2) when compared to
placebo; 1 when
compared to phar-
macotherapy; 1
when compared to
other control group.
Conjunctivitis 11 819 Timothy (4), grass mix SCIT vs. placebo (9), 10 studies showed 3 studies with low RofB High
symptoms (3), Parietaria (1), vs. pharmacotherapy greater improvement and 1 of these with
Alternaria (1), cat (1), (1), vs. SCIT (2) in symptoms in the strong magnitude; 4
multiple (1) both with appropri- SCIT group than the studies with medium
ate control groups comparator. RofB and strong magni-
tude; overall consistent
Combined 6 591 Grass mix (2), Alterna- SCIT vs. placebo (6), 5 studies showed 4 studies with low RofB High
symptom ria (1), timothy (1), vs. SIT (1) greater improvement and 2 of these with
score, nasal, mountain cedar (1), in symptoms in the strong magnitude; over-
ocular, bron- dust mite (1) SCIT group than the all consistent
chial; rhinitis comparator. 1 study
studies only showed improve-
ment in the SCIT
arm only when com-
paring initial to final
scores.
Rhinitis/rhino- 10 564 Dust mite (2), timothy SCIT vs. placebo (8), All studies showed 8 studies with medium Moderate
conjunctivitis (2), ragweed (1), vs. pharmacotherapy greater reduction in RofB and 6 of these
medication Parietaria (1), grass (1), vs. SCIT (3)all medication use in with strong magnitude;
scores mix (2), tree (1), mul- were placebo- the SCIT arm; 7 of overall consistent
tiple (1) controlled these were statisti-
cally significant: 6
when compared to
placebo, 1 when
compared to
pharmacotherapy.
Combined rhi- 11 768 Parietaria (3), timothy SCIT vs. placebo (11), 10 studies showed sig- 7 studies with low RofB High
nitis/rhinocon- (2), grass mix (3), vs. SCIT (1)pla- nificant reduction in and 4 of these with
junctivitis plus ragweed (1), Alterna- cebo-controlled asthma and rhino- strong magnitude; over-
asthma ria (1), dust mite (1) conjunctivitis all consistent

Erekosima et al.: Subcutaneous Immunotherapy Systematic Review

 TABLE I.
(Continued)
Strength of Evi- No. of No. of Allergens Comparators Summary of Strength of
dence Domains Studies Participants (No. of Studies) (No. of Studies) Findings Grading Data Evidence

medication medication con-

scores, rhinitis sumption in the
studies only SCIT group.
Combined rhi- 6 400 Grass mix (2), ragweed SCIT vs. placebo (6), 4 studies demon- 3 positive studies with Low
nitis with or (2), Alternaria (1), vs. SCIT (1)pla- strated greater medium RofB and only
without date tree (1) cebo-controlled improvement in the 1 has strong magnitude,
asthma, SCIT group than the whereas the other 2
symptom comparator. studies have moderate
medication magnitude; 1 negative

Laryngoscope 124: March 2014

score study with low RofB
and weak magnitude
Disease-spe- 4 539 Alternaria (1), Parietaria SCIT vs. placebo (4), All studies demon- 3 studies with low RofB High
cific quality of (1), timothy (1), grass vs. SCIT (1)pla- strated greater and strong magnitude;
life mix (1) cebo-controlled improvement in overall consistent
disease-specific
quality of life in the
SCIT group than
placebo.
Other outcomes
Nasal 6 114 Alternaria (1), tree mix SCIT vs. placebo (6), 3 studies demon- Not graded Not graded
provocation (1), grass mix (1), vs. SCIT (2)pla- strated significant
dust mite (1), rag- cebo-controlled decreases in nasal
weed (1), multiple (1) reactivity favoring
the SCIT group over
the comparison
group. 3 studies
showed improve-
ment in the SCIT
arm when compar-
ing initial to final
scores.
Conjunctival 7 127 Dust mite (2), birch (1), SCIT vs. placebo (4), 2 studies demon- Not graded Not graded
provocation cat (2), multiple (2) vs. SCIT (3) strated significant
decreases in ocular
reactivity favoring
the SCIT group over
the comparison
group.

The following evidence-grading scheme was used to grade the overall strength of evidence for each outcome: high-grade evidence 5 at least two trials having low risk of bias, at least one of which has a
strong magnitude of effect and the overall body of evidence is largely consistent; moderate grade evidence 5 one trial having a low risk of bias with a strong magnitude of effect; or two or more trials with
medium risk of bias having strong magnitudes of effect; or one trial having low risk of bias with moderate magnitude of effect plus one trial having medium risk of bias with strong magnitude of effect; and an
overall body of evidence that is largely consistent; low-grade evidence 5 there was evidence, but it did not meet the criteria for the above categories. Evidence was insufficient if there were no relevant trials.
RofB 5 risk of bias; SCIT 5subcutaneous immunotherapy.

621
Erekosima et al.: Subcutaneous Immunotherapy Systematic Review
scores.12,1923,26,28 All studies used a single allergen
for immunotherapy, with dust mite being the most
prevalent (in five studies).1923 Six were placebo-
controlled trials.1922,26,28 Five of eight demonstrated
greater reduction in medication use in the SCIT
group than the comparator, whereas two did not
report the direction of change. The strength of evi-
dence is high that SCIT reduces asthma medication
use (Supplementary Appendix B, Table 3).
Combined asthma plus rhinitis/rhinoconjunc-
tivitis medication scores. Three studies including 123
subjects reported combined asthma plus rhinoconjuncti-
vitis medication scores, each investigating a different
pollen.10,25,29 All study participants were adults. Two
were placebo-controlled,25,29 and one compared SCIT to
pharmacotherapy.10 All three demonstrated significant
reduction in asthma and rhinoconjunctivitis medication
consumption in the immunotherapy groups compared to
the comparison groups. The strength of evidence is mod-
erate that SCIT reduces asthma and rhinoconjunctivitis
medication consumption (Supplementary Appendix B,
Table 4).
Symptommedication scores. Four studies, enroll-
ing 111 individuals with asthma, reported combined
asthma or asthma plus rhinitis symptommedication
scores compared to a control group.11,28,30,32 Three were
placebo-controlled, and one compared SCIT to pharmaco-
therapy. All studies reported greater improvement in the
SCIT group than the comparator. Although the three
placebo-controlled studies reported statistically significant
improvement in SCIT compared to placebo, none
reported the magnitude of effect. The strength of
evidence is low to support that SCIT improves asthma
symptommedication scores (Supplementary Appendix B,
Table 5).
Secondary Outcomes
Pulmonary function testing. Eleven studies,
including 873 participants, reported changes in pulmo-
nary function test results.9,12,19,2224,26,27,29,31,33 Each
had a medium risk of bias. Study duration ranged from
3 months to 3 years; seven were placebo-controlled. The
findings were variable and inconsistent across studies.
Bronchial reactivity. Specific allergen broncho-
provocation tests were reported in 11 studies with 353
participants.11,20,26,27,29,30,3236 All demonstrated greater
improvement in the SCIT group than the comparator;
eight of these were reported as statistically significant
differences in bronchial sensitivity.11,20,26,29,3235
Nonspecific chemical bronchoprovocation tests were
reported by 13 studies, which included 568 partici-
pants.11,12,19,22,24,25,27,29,30,32,36,37 Overall, the direction of
effect was inconsistent, and only five studies demon-
strated greater improvement in the SCIT group than the
comparator.22,24,25,29
Rhinitis/Rhinoconjunctivitis Outcomes
Rhinitis/rhinoconjunctivitis symptoms. We
graded the strength of evidence using 23 RCTs that eval-
Laryngoscope 124: March 2014
622
uated SCIT for control of rhinitis/rhinoconjunctivitis
symptom scores in 1,479 participants.8,12,21,2527,3854
Most studies used a single allergen; only two used
multiple allergens. The most common allergens were
dust mite, Timothy grass, and grass mix, each used by
four studies. Twenty were placebo-controlled trials, and
20 consistently showed greater improvement in the SCIT
group than the comparator. The strength of evidence is
high to support that SCIT improves rhinitis/rhinoconjunc-
tivitis symptoms (Supplementary Appendix B, Table 6).
Conjunctivitis symptoms. Eleven studies eval-
uated conjunctivitis symptom scores in 819 sub-
jects.8,25,27,3840,48,49,51,53,55 Nine were placebo-controlled.
Most used a single allergen; only one used multiple
allergens. The most prevalent allergen was grass (Timo-
thy in four and grass mix in three). Ten of 11 studies
demonstrated greater improvement in symptoms in the
SCIT group than the comparator. The overall strength of
evidence is high to support that SCIT improves allergic
conjunctivitis symptoms (Supplementary Appendix B,
Table 7).
Combined symptom scores (nasal, ocular, and
bronchial). Six studies reported combined scores
including nasal, ocular, and bronchial symptom scores in
591 participants.39,41,53,5658 Although many of these
patients did not have an objective diagnosis of asthma,
they had bronchial symptoms at baseline. All were
placebo-controlled trials. Five studies showed greater
improvement in combined symptom scores in the SCIT
group than the comparator. The strength of evidence is
high to support that SCIT improves combined (nasal,
ocular, and bronchial) symptoms scores (Supplementary
Appendix B, Table 8).
Rhinitis/rhinoconjunctivitis medication scores.
Rhinitis/rhinoconjunctivitis medication scores were
reported in 10 studies including 564 subjects.8,38,40,42
44,48,50,52,55
Most were single-allergen studies with only
one multiple-allergen study. Eighty percent were
placebo-controlled studies. All studies showed greater
improvement in the SCIT group than the comparator.
The strength of evidence is moderate to support that
SCIT decreases medication use for rhinitis/rhinoconjunc-
tivitis (Supplementary Appendix B, Table 9).
Combined rhinitis/rhinoconjunctivitis plus
asthma medication scores. Eleven studies evaluated
combined medication scores in 768 partici-
pants.38,39,41,4547,51,53,5557 All were placebo-controlled
trials, and all used a single allergen. Ten studies showed
greater reduction in medication use in the SCIT group
than the comparator. The strength of evidence is high to
support that SCIT decreases combined medication use
(Supplementary Appendix B, Table 10).
Rhinitis/rhinoconjunctivitis symptommedica-
tion scores. Six studies reported combined rhinitis/rhi-
noconjunctivitis symptommedication scores in 400
participants.53,56,5962 All were placebo-controlled trials
using single allergens. Four studies demonstrated
greater improvement in the SCIT group than the com-
parator. The strength of evidence is low to support that
SCIT improves symptommedication scores (Supplemen-
tary Appendix B, Table 11).
Erekosima et al.: Subcutaneous Immunotherapy Systematic Review

Safety of Subcutaneous Immunotherapy Evidence Summary Table.
Type of Event Allergen (No. of Studies)
Local reactions, reported Dust mite (2), Alternaria
as patients; 11 studies (1), Cladosporium (1),
grass mix (2), ragweed
(2), cat (2), tree mix (1);
1 study reported AEs in
the control arm
Local reactions, reported Dust mite (1), cat (2), dog
Laryngoscope 124: March 2014
as events; 10 studies (1), grass mix (1), timo-
thy (1), ragweed (1),
Parietaria (1), Alternaria
(1), multiple (1); 5 stud-
ies reported AEs in the
control arm
Cutaneous reactions, Timothy (3), dust mite (1),
reported as patients; 8 Alternaria (1), Parietaria
studies (1), cat (1); 2 studies
reported AEs in the
control arm
Respiratory reactions, Dust mite (4), timothy (3),
reported as patients; 13 Alternaria (2), Parietaria
studies (1), multiple (1); 6 stud-
ies reported AEs in the
control arm2 studies
reported AEs only in the
control arm
Respiratory reactions, Birch (1), Cladosporium
reported as events; 3 (1), cat (1); 3 studies
studies reported AEs in the
control arm
GI reactions, reported as Timothy (1); no studies
patients; 1 study reported AEs in the
control arm
General symptoms, Timothy (5), ragweed (2),
reported as patients; 14 dust mite (2), grass mix
studies (2), cat (1), Cladospo-
rium (1), Parietaria (1); 7
studies reported AEs in
the control arm
623
Erekosima et al.: Subcutaneous Immunotherapy Systematic Review
TABLE II.
Number of Patients in Studies
Reporting AEs
SCIT arm: 346 patients
Control arm: 7 patients; 1
study
SCIT arm: 144 patients,
1,680 injections
Control arm: 86 patients,
706 injections; 3 studies
510 patients in 4 studies
that did not report num-
ber of injections; SCIT
arm: 389; control arm:
121; 2 studies
SCIT arm: 389 patients
Control arm: 48 patients;
2 studies
SCIT arm: 652 patients
Control arm: 208 patients;
6 studies
SCIT arm: 37 patients,
444 injections
Control arm: 37 patients,
588 injections; 2 studies
22 patients in 2 studies
that did not report num-
ber of injections; SCIT
arm: 11; control arm: 11
SCIT arm: 20 patients
SCIT arm: 624 patients
Control arm: 217 patients;
6 studies
SCIT arm: 48 patients
Number of Patients With
Harms Range of AEs Severity [%]
SCIT arm: 71 patients pre- SCIT arm: range 5 5% Unspecified [77], mild [14],
senting AEs 58% moderate [6], severe [3]
Control arm:1 patient pre- Control arm: 14% Unspecified [100]
senting AEs
SCIT arm: 127 reactions SCIT arm: range 5 3% Unspecified [29], mild [68],
reported 9.7% moderate [3]
Control arm: 16 reactions Control arm: range 5 2% Unspecified [75], mild [25]
reported 3%
293 reactions reported in Percentage and range not Mild [72], moderate [11],
these 2 studies; SCIT quantifiable unspecified [17]
arm: 70; control arm:
16; arm not specified:
207
SCIT arm: 41 patients pre- SCIT arm: range 5 2% Unspecified [61], mild [12],
senting AEs 25% moderate [27]
Control arm: 13 patients Control arm: range 16% Unspecified [23], mild [77]
presenting AEs 33%
SCIT arm: 178 patients SCIT arm: range 5 1% Unspecified [73], mild [16],
presenting AEs 71% moderate [11]
Control arm: 56 patients Control arm: range 5 1% Unspecified [93], mild [7]
presenting AEs 88%
SCIT arm: 80 reactions SCIT arm: range 5 2% Mild [100]
reported 27%
Control arm: 84 reactions Control arm: range 5 2% Mild [100]
reported 19%
59 reactions reported in Percentage not Mild [88], moderate [12]
these 2 studies; SCIT quantifiable
arm: 32; control arm: 27
SCIT arm: 1 patient pre- 5% Mild [100]
senting AEs
SCIT arm: 190 patients SCIT arm: range 5 3.5% Unspecified [74], mild [12],
presenting AEs 44% moderate [10], severe
[4]
Control arm:52 patients Control arm: Unspecified [83], mild [5],
presenting AEs range 5 3.5%35% moderate [10], severe
[2]
SCIT arm: 78 reactions Percentage and range not Mild [100]
reported quantifiable
 Unspecified [36], mild [24],
Quality of life. Quality of life was reported in four

Unspecified [50], moder-

moderate [32], severe
placebo-controlled trials including 539 subjects.39,53,55,57

ate [34], severe [16]

Each used a single allergen. The instruments used to

Unspecified [100]
assess quality of life were validated, disease-specific
instruments including the Rhinoconjunctivitis Quality of

Severe [100]
Life questionnaire and/or the Short Form 36 question-
Severity [%]

Mild [100]

naire. All studies demonstrated greater improvement in

the SCIT group than placebo. There is high-grade
[8] evidence to support the use of SCIT to improve disease-
specific quality of life among individuals with
rhinitis/rhinoconjunctivitis (Supplementary Appendix B,
Percentage and range not

1.123 events per patient

Table 12).
range 5 10%17%
range 5 2%53%

Secondary Outcomes
SCIT arm: range
quantifiable

0.7%26% Nasal and conjunctival allergen challenge

Control arm:
Range of AEs

(provocation). Thirteen SCIT studies challenged sub-

SCIT arm:

jects with specific allergens to quantify symptoms. Six

studies used nasal provocation.10,23,30,43,48,63 Seven stud-
ies used conjunctival provocation tests.20,21,29,31,32,64,65
One of the nasal provocation studies reported significant
SCIT arm: 79 patients pre-

improvement in symptoms after SCIT compared to pla-

Control arm: 81 reactions

Control arm: 12 patients

cebo or when comparing post-treatment to pretreatment

SCIT arm: 13 reactions
511 reactions reported
Number of Patients With

response.30 Two of the conjunctival provocation studies

presenting AEs

demonstrated significant improvement in symptoms

after SCIT compared with placebo or with comparison of
senting AEs

post-treatment to pretreatment response.21,32

reported

reported

Sensitivity analysis. Analysis of the data with

Harms

exclusion of the studies that enrolled both adults and

(Continued)
TABLE II.

children changed the evidence grade for only two

asthma outcomes. The strength of evidence regarding
reduction in asthma medication use changes from high
that did not report num-
Number of Patients in Studies

Control arm: 103 patients;

Control arm: 22 patients;

grade to low grade with exclusion of the mixed popula-

46 patients in 2 studies
SCIT arm: 373 patients

SCIT arm: 205 patients

tion studies.19,22,23 The evidence grade changes to insuf-

ber of injections

ficient for the asthma symptommedication score

outcome with exclusion of the three studies that
Reporting AEs

AE 5 adverse event; GI 5 gastrointestinal; SCIT 5subcutaneous immunotherapy.

included children.11,30,32 All other primary outcomes,

2 studies
1 study

including all rhinitis/rhinoconjunctivitis outcomes, were

unaffected.

Evidence for the Safety of SCIT

reported AEs only in the

Thirty-five of the 61 included SCIT studies reported

studies reported AEs in
grass mix (1); 2 studies

Dust mite (2), timothy (1),

Birch (1), grass mix (1); 1

(2), timothy (2), cat (1),

phylaxis in the control

study reported AEs in

studies reported ana-

data.8,11,14,16,17,2427,2935,3739,4144,48,49,51,53
control arm1 study
Ragweed (3), dust mite

Cladosporium (1); no

safety
Cat (1), multiple (1); no
reported AEs in the
Allergen (No. of Studies)

55,59,60,62,6668
Local reactions were common, occurring in
the control arm

the control arm

5% to 58% of patients and 3% to 10% of injections

(Table II). The most common systemic reactions were
control arm

respiratory reactions, occurring in up to 71% of patients

in the SCIT group versus 88% of control patients and in
arm

up to 27% of injections. General symptoms (such as

headache, fatigue, and arthritis) and unspecified reac-
tions also occurred frequently, affecting up to 44% and
53% of patients, respectively. The majority of reactions,
reported as patients; 10

Anaphylactic reactions; 4

both local and systemic, were of mild or unspecified

reported as events; 2
reported as events;2

Unspecified reactions,

Unspecified reactions,

severity. Thirteen anaphylactic reactions were reported

General symptoms,

in four trials. No deaths were reported.

Type of Event

DISCUSSION
studies

studies

studies

studies

Evidence supports the effectiveness and safety of

SCIT for treatment of allergic rhinoconjunctivitis and
asthma. We found high-grade evidence that SCIT

Laryngoscope 124: March 2014 Erekosima et al.: Subcutaneous Immunotherapy Systematic Review
624
improves asthma symptoms, asthma medication usage,
rhinitis/rhinoconjunctivitis symptoms, conjunctivitis
symptoms, and rhinitis/rhinoconjunctivitis disease-
specific quality of life in comparison to placebo or usual
care. There is moderate evidence that SCIT decreases
rhinitis/rhinoconjunctivitis medication usage.
Our findings are consistent with previous system-
atic reviews,6971 which have demonstrated that SCIT
provides a significant reduction in asthma symptoms
and asthma medications,69 provides a significant reduc-
tion in rhinitis symptom scores and medication use with
a low risk of adverse events,70 and is at least as potent
as pharmacotherapy in controlling rhinitis symptoms.71
In contrast to previous systematic reviews,6971 our study
reports on the breadth of allergic rhinoconjunctivitis and
asthma outcomes, including combined rhinoconjunctivitis
and asthma outcomes not previously reported. Our review
includes 10 studies (one asthma,22 five rhinitis/rhinocon-
junctivitis,18,39,42,61,64 and four asthma plus rhinitis/rhi-
noconjunctivitis studies16,37,53,62) that were published
after the most recent Cochrane reviews on these
topics.69,70 Guidelines for allergen immunotherapy trials
recommend that the combined symptommedication score
be used as the primary outcome measure.72 Few studies
or reviews have reported this outcome measure.
When evaluating the magnitude of effect for indi-
vidual studies, there is no consensus on what is a clini-
cally relevant improvement in a measured outcome. The
World Allergy Organization taskforce recommends that
the minimal clinically relevant efficacy should be at
least 20% higher than placebo.72 Although the taskforce
refers to placebo-controlled studies, our review included
studies comparing SCIT to pharmacotherapy; for these
studies, we would expect a smaller difference. Hence, we
considered that a 15% improvement indicates a moder-
ate magnitude of effect for the purposes of clinical deci-
sion making; <15% is weak.
Most of the included trials used a single allergen
for immunotherapy; hence, it is difficult to determine
the extent to which this evidence applies to multiple-
allergen regimens, which are commonly used in the
United States. Enrolled participants in these studies
had mild or moderate asthma; the generalizability of
these findings for patients with more severe asthma is
uncertain.
We acknowledge limitations posed by these data. A
meta-analysis was not performed due to substantial het-
erogeneity of the included studies. There was extreme
variability in outcomes reported, scoring of primary out-
comes, allergen dosing, treatment schedules, and meth-
ods of reporting safety data. Additionally, relevant
statistical information on precision was frequently
unavailable; therefore, the data could not be pooled to
perform a meta-analysis. Our grading system was uti-
lized to overcome these obstacles.
We included only RCTs in this review, and yet the
studies varied substantially in their risks of bias.
Although all studies used randomization, several stud-
ies did not specify whether allocation schemes were
concealed, or if the type of intervention was concealed
from the participants and outcomes assessors. Half of
Laryngoscope 124: March 2014 Erekosima et al.: Subcutaneous Immunotherapy Systematic Review
the studies received industry support, and yet authors
rarely stated the role or extent of involvement of their
sponsors. The studies used varying criteria for diagnos-
ing asthma and assessing asthma severity and control.
Some studies that reported combined asthma and rhino-
conjunctivitis scores demonstrated significant improve-
ment, but a preferential effect of SCIT on one disease
process may have highly influenced the combined scores.
Studies with multiple allergens presented a similar
dilemma; response to one allergen may have determined
the overall clinical score, and the true effect of desensiti-
zation to each allergen remains unclear.
We considered publication bias as a possible limita-
tion. We searched for registered but unpublished clinical
trials and requested scientific packets from pharmaceuti-
cal companies to identify unpublished trials. However,
we did not identify any additional studies, and our
review includes studies in the period before clinical trial
registration was required. The lack of adequate statisti-
cal information to pool the data did not allow for assess-
ment of publication bias.
We caution that our study reports only the safety
data from RCTs, and is not a comprehensive review of
the prevalence of adverse events, which would require
the review of nonrandomized studies and case reports.
Additional RCTs are needed to strengthen the evidence
for the efficacy and safety of SCIT. Future studies
should use standardized methods to report primary clini-
cal outcome measures, adverse events, allergen doses,
dosing frequency, and treatment duration as well as a
uniform method of assessing clinical efficacy, as recom-
mended in published guidelines for allergen immuno-
therapy trials.7274 Future studies should have clear
concealment of allocation and masking of the interven-
tion throughout the study to reduce bias. Given increas-
ing discussion in the scientific community on the clinical
use and efficacy of single-allergen versus multiple-
allergen regimens, additional studies with head-to-head
comparisons of single-allergen versus multiple-allergen
regimens are needed. Reporting results by asthma sever-
ity would be useful for assessing whether there is a sub-
group of patients with asthma that may particularly
benefit from immunotherapy.
When applying the results of this systematic review
to clinical practice, the risk/benefit ratio of SCIT must be
kept in mind. Although our study was limited to the
safety data of RCTs, a recent update on the safety of spe-
cific immunotherapy75 reviewed the previous literature
and found the likelihood of fatalities from SCIT to be one
in 22.5 million doses, and 17 fatalities occurred from
1990 to 2001. The risk of death from SCIT, although very
rare, must be taken in consideration when reviewing
treatment recommendations and shared with patients.
The decision to start SCIT should be made on a case-by-
case basis, looking at the potential improvement in
symptoms and the risks involved.
CONCLUSION
We found moderate to strong evidence to support
the effectiveness of SCIT for treatment of allergic
625
rhinoconjunctivitis and asthma, particularly using
single-allergen immunotherapy regimens. Adverse reac-
tions to SCIT are common, but no deaths were reported
in the included studies. Strengthening the evidence for
the effectiveness and safety of multiple-allergen regi-
mens should be high priority for future studies.
Acknowledgment
The authors thank Peter S. Creticos, MD, N. Franklin
Adkinson, MD, Daniela Vollenweider, MD, and Darcy Ward,
MS (Department of Medicine, Johns Hopkins University
School of Medicine, Baltimore, Maryland), who contributed
greatly to the selection of articles. Drs. Creticos and Adkin-
son also were instrumental in developing the initial protocol
for this review. Dr. Creticos was the initial principal investi-
gator. Per the funders (AHRQ) request, to ensure compli-
ance with established AHRQ conflict of interest policy
including perceived conflicts of interest, Drs. Creticos and
Adkinson were recused from review activities including
data extraction, assessment of study quality, and report
writing, due to their prior consulting arrangements. These
individuals received support through grant funding from
the AHRQ during the time of their contributions.
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