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The Laryngoscope

C 2013 The American Laryngological,


V
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-


INTRODUCTION
ment of Medicine (N.E.), Department of Medicine (C.S.-C., Y.C., J.B.S.), Allergic rhinitis affects 10% to 30% of adults in the
Department of OtolaryngologyHead and Neck Surgery (M.R., S.Y.L.), and United States.1 Asthma affects 9% of the US population,
Department of Pediatrics (J.M.K.), Johns Hopkins University School of
Medicine, Baltimore, Maryland, U.S.A and approximately 62% of individuals with asthma have
Editors Note: This Manuscript was accepted for publication June atopy.2 Allergen immunotherapy is typically recom-
14, 2013. mended for patients whose allergic rhinoconjunctivitis
The authors have no other funding, financial relationships, or con- and asthma symptoms cannot be controlled by environ-
flicts of interest to disclose.
S.Y.L. serves as a consultant for Wellpoint Consulting. This study
mental measures and pharmacotherapy or those who do
was funded by the Agency for Healthcare Research and Quality (AHRQ). not tolerate or adhere to their medication regimens.3
AHRQ staff participated in formulating the key questions and Subcutaneous immunotherapy (SCIT), first intro-
reviewed planned methods and data analyses, as well as interim and
final evidence reports. They had no role in study selection, quality rat- duced by Noon in 1911 as a means of treating allergic
ings, or interpretation and synthesis of the evidence. symptomatology,4 involves administering increasing
The authors of this article are responsible for its contents, includ-
ing any clinical or treatment recommendations. No statement in this
doses of an allergen-containing extract to suppress or
article should be construed as an official position of AHRQ or of the US eliminate allergic symptoms through modulation of a
Department of Health and Human Services. This research was con- patients immune system. Recent approaches with modi-
ducted by the Johns Hopkins University Evidence-Based Practice Center
under contract to the AHRQ, Rockville, Maryland. fied and recombinant allergens, immunostimulatory
Send correspondence to Sandra Y. Lin, MD, 601 N. Caroline adjuvants, T-celltolerizing constructs, and improved
Street, #6254, Baltimore, MD 21287. E-mail: slin30@jhmi.edu
oral approaches have shown promise for treatment of
DOI: 10.1002/lary.24295 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 we extracted the outcomes at peak pollen seasons when
the United States.5 Other delivery routes such as sublin- available.
gual, intranasal, epicutaneous, intrabronchial, and intra- Two reviewers independently assessed the risk of bias in
lymphatic are also currently considered investigational each article and came to consensus about the overall rating. We
used a modification of the Cochrane Collaboration Tool for
in the United States,5 although sublingual immunother-
Assessing Risk of Bias from the Cochrane Handbook for Sys-
apy is prescribed off-label by some practitioners. tematic Reviews of Interventions.6 Studies were categorized as
In this study, we sought to review the evidence for having a low, moderate, or high risk of bias.
the effectiveness and safety of SCIT for treatment of
adults with allergic rhinitis/rhinoconjunctivitis and/or
asthma, focusing on SCIT formulations that are avail- Data Synthesis and Analysis
able in the United States. This review is part of an evi- We summarized the studies by outcomes, by comparators,
dence report commissioned by the US Agency for and then by allergen. Given the substantial heterogeneity
Healthcare Research and Quality (AHRQ). 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-
MATERIALS AND METHODS
mended by the Guide for Conducting Comparative
We recruited technical experts for input on the research
Effectiveness Reviews.6,7 The magnitude of effect was classi-
questions and search strategy. We developed a protocol
fied according to the percentage difference in before to after
and posted it online, following guidelines for systematic
change comparing the SCIT group and comparator group;
review (http://effectivehealthcare.ahrq.gov/ehc/products/270/
<15% was defined as a weak difference, a 15% to 40% differ-
665/SIT_Protocol_20110824.pdf). Additional methods details
ence as moderate, and >40% as a strong effect. The body of
are in the full AHRQ Evidence Report, which can be accessed evidence for each primary outcome was graded as 1) high
online at http://effectivehealthcare.ahrq.gov/search-for-guides- grade, 2) moderate grade, 3) low grade, or 4) insufficient.6,7
reviews-and-reports/?pageaction5displayproduct&productID5 The evidence grade reflects the likelihood that additional
1427&ECem5130327. 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
Data Sources and Searches trials with low risk of bias, and at least one strong magnitude
We searched the following databases rigorously: MEDLINE of effect in the context of largely consistent overall evidence.
(from 1950 to May 21, 2012), Embase (from 1947 to May 21, Moderate-grade evidence required one or more trials with low
2012), Cochrane Central Register of Controlled Trials (to May 21, risk of bias and strong magnitude of effect, or at least two tri-
2012), and LILACS (from 1982 to May 21 2012; Supplementary als with medium risk of bias and strong magnitude of effect, or
Methods: Search Strategy). We also searched public registries of one trial having low risk of bias with moderate magnitude of
clinical trials (www.clinicaltrials.gov) and requested Scientific effect plus one trial having medium risk of bias with strong
Information Packets from relevant pharmaceutical companies. 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
Study Selection measures (pulmonary function test results and provocation
We reviewed titles and then abstracts to identify random- tests) was not graded.
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 RESULTS
diagnoses were confirmed with objective testing. The trials We identified 7,746 potentially relevant citations.
must have tested SCIT alone or in combination with usual care, Sixty-one RCTs (12 asthma, 23 rhinitis/rhinoconjunctivi-
which included pharmacotherapy and environmental interven- tis, and 26 combined asthma and rhinitis/rhinoconjunc-
tions. We included trials if the comparators were placebo, other tivitis studies) including 3,577 subjects met criteria for
SCIT regimens, or pharmacotherapy. For inclusion, the trials inclusion (Fig. 1). Supplementary Appendix A describes
must have reported symptoms, medication use, results of provo- the characteristics of the individual studies.
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 Study and Population Characteristics
available in English. We also excluded studies that did not
The studies were published between 1967 and
clearly report the dose of allergen delivered.
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
Data Extraction and Quality Assessment
(72%) were placebo-controlled (36 were designed as
Outcomes of interest included symptom scores, medication
SCIT vs. placebo; eight comparing different SCIT regi-
scores, combined symptom and medication scores, quality of
life, and safety or harms. Asthma outcomes were extracted only
mens also included a placebo arm); 11 were SCIT ver-
if subjects in the study were diagnosed with asthma using sus SCIT; and one compared SCIT versus an untreated
objective criteria, or according to established clinical guidelines. control group. Only five studies were specifically
For studies that recorded outcomes at multiple time designed to compare SCIT versus pharmacotherapy.812
points, we used the outcome data from the final time point However, most studies (75%) allowed the use of medica-
reported. For studies assessing subjects during a single season, tions, either routinely or as needed for symptom

Laryngoscope 124: March 2014 Erekosima et al.: Subcutaneous Immunotherapy Systematic Review
617
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.

control; others did not state whether medications were pants.1928 All used a single allergen, with dust mites
allowed. studied in six studies. Eighty percent were placebo-
Forty studies used a single allergen for immuno- controlled trials. Ninety percent of studies demonstrated
therapy, whereas the remaining 21 studies used multiple a greater improvement in the SCIT group than the com-
allergens. The majority (38 studies or 62%) evaluated parator. The strength of evidence is high to support that
seasonal allergens including trees, grasses, weeds, and SCIT improves asthma symptom scores (Supplementary
seasonal molds; 23 studies (38%) evaluated perennial Appendix B, Table 1).
allergens. Allergen doses varied across studies.
Combined asthma plus rhinitis/rhinoconjunc-
Seventeen studies (28%) had a low risk of bias. Thirty-
tivitis symptoms. Five asthma studies including 175
four studies (56%) were assessed as having a medium risk
participants reported combined asthma plus rhinocon-
of bias, and 10 studies (16%) had a high risk of bias.
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-
Evidence for Effectiveness of SCIT
trolled25,2931; one compared SCIT to pharmacotherapy.
Table I summarizes the findings according to out-
All studies demonstrated greater improvement in the
comes. Six of the included studies were not graded
SCIT groups than the comparator. The strength of evi-
because all study arms received immunotherapy.1318
dence is moderate to support that SCIT improves com-
bined asthma and rhinoconjunctivitis symptom scores
(Supplementary Appendix B, Table 2).
Asthma Outcomes
Asthma symptoms. Ten studies evaluated SCIT for Asthma medication use. Eight studies, includ-
control of asthma symptoms, including 628 partici- ing 592 subjects, reported asthma medication

Laryngoscope 124: March 2014 Erekosima et al.: Subcutaneous Immunotherapy Systematic Review
618
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.

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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.

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Erekosima et al.: Subcutaneous Immunotherapy Systematic Review
scores.12,1923,26,28 All studies used a single allergen uated SCIT for control of rhinitis/rhinoconjunctivitis
for immunotherapy, with dust mite being the most symptom scores in 1,479 participants.8,12,21,2527,3854
prevalent (in five studies).1923 Six were placebo- Most studies used a single allergen; only two used
controlled trials.1922,26,28 Five of eight demonstrated multiple allergens. The most common allergens were
greater reduction in medication use in the SCIT dust mite, Timothy grass, and grass mix, each used by
group than the comparator, whereas two did not four studies. Twenty were placebo-controlled trials, and
report the direction of change. The strength of evi- 20 consistently showed greater improvement in the SCIT
dence is high that SCIT reduces asthma medication group than the comparator. The strength of evidence is
use (Supplementary Appendix B, Table 3). high to support that SCIT improves rhinitis/rhinoconjunc-
Combined asthma plus rhinitis/rhinoconjunc- tivitis symptoms (Supplementary Appendix B, Table 6).
tivitis medication scores. Three studies including 123 Conjunctivitis symptoms. Eleven studies eval-
subjects reported combined asthma plus rhinoconjuncti- uated conjunctivitis symptom scores in 819 sub-
vitis medication scores, each investigating a different jects.8,25,27,3840,48,49,51,53,55 Nine were placebo-controlled.
pollen.10,25,29 All study participants were adults. Two Most used a single allergen; only one used multiple
were placebo-controlled,25,29 and one compared SCIT to allergens. The most prevalent allergen was grass (Timo-
pharmacotherapy.10 All three demonstrated significant thy in four and grass mix in three). Ten of 11 studies
reduction in asthma and rhinoconjunctivitis medication demonstrated greater improvement in symptoms in the
consumption in the immunotherapy groups compared to SCIT group than the comparator. The overall strength of
the comparison groups. The strength of evidence is mod- evidence is high to support that SCIT improves allergic
erate that SCIT reduces asthma and rhinoconjunctivitis conjunctivitis symptoms (Supplementary Appendix B,
medication consumption (Supplementary Appendix B, Table 7).
Table 4). Combined symptom scores (nasal, ocular, and
Symptommedication scores. Four studies, enroll- bronchial). Six studies reported combined scores
ing 111 individuals with asthma, reported combined including nasal, ocular, and bronchial symptom scores in
asthma or asthma plus rhinitis symptommedication 591 participants.39,41,53,5658 Although many of these
scores compared to a control group.11,28,30,32 Three were patients did not have an objective diagnosis of asthma,
placebo-controlled, and one compared SCIT to pharmaco- they had bronchial symptoms at baseline. All were
therapy. All studies reported greater improvement in the placebo-controlled trials. Five studies showed greater
SCIT group than the comparator. Although the three improvement in combined symptom scores in the SCIT
placebo-controlled studies reported statistically significant group than the comparator. The strength of evidence is
improvement in SCIT compared to placebo, none high to support that SCIT improves combined (nasal,
reported the magnitude of effect. The strength of ocular, and bronchial) symptoms scores (Supplementary
evidence is low to support that SCIT improves asthma Appendix B, Table 8).
symptommedication scores (Supplementary Appendix B, Rhinitis/rhinoconjunctivitis medication scores.
Table 5). 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
Secondary Outcomes one multiple-allergen study. Eighty percent were
Pulmonary function testing. Eleven studies, placebo-controlled studies. All studies showed greater
including 873 participants, reported changes in pulmo- improvement in the SCIT group than the comparator.
nary function test results.9,12,19,2224,26,27,29,31,33 Each The strength of evidence is moderate to support that
had a medium risk of bias. Study duration ranged from SCIT decreases medication use for rhinitis/rhinoconjunc-
3 months to 3 years; seven were placebo-controlled. The tivitis (Supplementary Appendix B, Table 9).
findings were variable and inconsistent across studies. Combined rhinitis/rhinoconjunctivitis plus
Bronchial reactivity. Specific allergen broncho- asthma medication scores. Eleven studies evaluated
provocation tests were reported in 11 studies with 353 combined medication scores in 768 partici-
participants.11,20,26,27,29,30,3236 All demonstrated greater pants.38,39,41,4547,51,53,5557 All were placebo-controlled
improvement in the SCIT group than the comparator; trials, and all used a single allergen. Ten studies showed
eight of these were reported as statistically significant greater reduction in medication use in the SCIT group
differences in bronchial sensitivity.11,20,26,29,3235 than the comparator. The strength of evidence is high to
Nonspecific chemical bronchoprovocation tests were support that SCIT decreases combined medication use
reported by 13 studies, which included 568 partici- (Supplementary Appendix B, Table 10).
pants.11,12,19,22,24,25,27,29,30,32,36,37 Overall, the direction of Rhinitis/rhinoconjunctivitis symptommedica-
effect was inconsistent, and only five studies demon- tion scores. Six studies reported combined rhinitis/rhi-
strated greater improvement in the SCIT group than the noconjunctivitis symptommedication scores in 400
comparator.22,24,25,29 participants.53,56,5962 All were placebo-controlled trials
using single allergens. Four studies demonstrated
greater improvement in the SCIT group than the com-
Rhinitis/Rhinoconjunctivitis Outcomes parator. The strength of evidence is low to support that
Rhinitis/rhinoconjunctivitis symptoms. We SCIT improves symptommedication scores (Supplemen-
graded the strength of evidence using 23 RCTs that eval- tary Appendix B, Table 11).

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622
TABLE II.
Safety of Subcutaneous Immunotherapy Evidence Summary Table.
Number of Patients in Studies Number of Patients With
Type of Event Allergen (No. of Studies) Reporting AEs Harms Range of AEs Severity [%]

Local reactions, reported Dust mite (2), Alternaria SCIT arm: 346 patients SCIT arm: 71 patients pre- SCIT arm: range 5 5% Unspecified [77], mild [14],
as patients; 11 studies (1), Cladosporium (1), senting AEs 58% moderate [6], severe [3]
grass mix (2), ragweed
(2), cat (2), tree mix (1); Control arm: 7 patients; 1 Control arm:1 patient pre- Control arm: 14% Unspecified [100]
study senting AEs
1 study reported AEs in
the control arm
Local reactions, reported Dust mite (1), cat (2), dog SCIT arm: 144 patients, SCIT arm: 127 reactions SCIT arm: range 5 3% Unspecified [29], mild [68],

Laryngoscope 124: March 2014


as events; 10 studies (1), grass mix (1), timo- 1,680 injections reported 9.7% moderate [3]
thy (1), ragweed (1), Control arm: 86 patients, Control arm: 16 reactions Control arm: range 5 2% Unspecified [75], mild [25]
Parietaria (1), Alternaria 706 injections; 3 studies reported 3%
(1), multiple (1); 5 stud-
ies reported AEs in the 510 patients in 4 studies 293 reactions reported in Percentage and range not Mild [72], moderate [11],
control arm that did not report num- these 2 studies; SCIT quantifiable unspecified [17]
ber of injections; SCIT arm: 70; control arm:
arm: 389; control arm: 16; arm not specified:
121; 2 studies 207
Cutaneous reactions, Timothy (3), dust mite (1), SCIT arm: 389 patients SCIT arm: 41 patients pre- SCIT arm: range 5 2% Unspecified [61], mild [12],
reported as patients; 8 Alternaria (1), Parietaria senting AEs 25% moderate [27]
studies (1), cat (1); 2 studies
reported AEs in the Control arm: 48 patients; Control arm: 13 patients Control arm: range 16% Unspecified [23], mild [77]
control arm 2 studies presenting AEs 33%
Respiratory reactions, Dust mite (4), timothy (3), SCIT arm: 652 patients SCIT arm: 178 patients SCIT arm: range 5 1% Unspecified [73], mild [16],
reported as patients; 13 Alternaria (2), Parietaria presenting AEs 71% moderate [11]
studies (1), multiple (1); 6 stud-
ies reported AEs in the Control arm: 208 patients; Control arm: 56 patients Control arm: range 5 1% Unspecified [93], mild [7]
6 studies presenting AEs 88%
control arm2 studies
reported AEs only in the
control arm
Respiratory reactions, Birch (1), Cladosporium SCIT arm: 37 patients, SCIT arm: 80 reactions SCIT arm: range 5 2% Mild [100]
reported as events; 3 (1), cat (1); 3 studies 444 injections reported 27%
studies reported AEs in the Control arm: 37 patients, Control arm: 84 reactions Control arm: range 5 2% Mild [100]
control arm 588 injections; 2 studies reported 19%
22 patients in 2 studies 59 reactions reported in Percentage not Mild [88], moderate [12]
that did not report num- these 2 studies; SCIT quantifiable
ber of injections; SCIT arm: 32; control arm: 27
arm: 11; control arm: 11
GI reactions, reported as Timothy (1); no studies SCIT arm: 20 patients SCIT arm: 1 patient pre- 5% Mild [100]
patients; 1 study reported AEs in the senting AEs
control arm
General symptoms, Timothy (5), ragweed (2), SCIT arm: 624 patients SCIT arm: 190 patients SCIT arm: range 5 3.5% Unspecified [74], mild [12],
reported as patients; 14 dust mite (2), grass mix presenting AEs 44% moderate [10], severe
studies (2), cat (1), Cladospo- [4]
rium (1), Parietaria (1); 7
studies reported AEs in Control arm: 217 patients; Control arm:52 patients Control arm: Unspecified [83], mild [5],
the control arm 6 studies presenting AEs range 5 3.5%35% moderate [10], severe
[2]
SCIT arm: 48 patients SCIT arm: 78 reactions Percentage and range not Mild [100]
reported quantifiable

623
Erekosima et al.: Subcutaneous Immunotherapy Systematic Review
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, the studies received industry support, and yet authors
rhinitis/rhinoconjunctivitis symptoms, conjunctivitis rarely stated the role or extent of involvement of their
symptoms, and rhinitis/rhinoconjunctivitis disease- sponsors. The studies used varying criteria for diagnos-
specific quality of life in comparison to placebo or usual ing asthma and assessing asthma severity and control.
care. There is moderate evidence that SCIT decreases Some studies that reported combined asthma and rhino-
rhinitis/rhinoconjunctivitis medication usage. conjunctivitis scores demonstrated significant improve-
Our findings are consistent with previous system- ment, but a preferential effect of SCIT on one disease
atic reviews,6971 which have demonstrated that SCIT process may have highly influenced the combined scores.
provides a significant reduction in asthma symptoms Studies with multiple allergens presented a similar
and asthma medications,69 provides a significant reduc- dilemma; response to one allergen may have determined
tion in rhinitis symptom scores and medication use with the overall clinical score, and the true effect of desensiti-
a low risk of adverse events,70 and is at least as potent zation to each allergen remains unclear.
as pharmacotherapy in controlling rhinitis symptoms.71 We considered publication bias as a possible limita-
In contrast to previous systematic reviews,6971 our study tion. We searched for registered but unpublished clinical
reports on the breadth of allergic rhinoconjunctivitis and trials and requested scientific packets from pharmaceuti-
asthma outcomes, including combined rhinoconjunctivitis cal companies to identify unpublished trials. However,
and asthma outcomes not previously reported. Our review we did not identify any additional studies, and our
includes 10 studies (one asthma,22 five rhinitis/rhinocon- review includes studies in the period before clinical trial
junctivitis,18,39,42,61,64 and four asthma plus rhinitis/rhi- registration was required. The lack of adequate statisti-
noconjunctivitis studies16,37,53,62) that were published cal information to pool the data did not allow for assess-
after the most recent Cochrane reviews on these ment of publication bias.
topics.69,70 Guidelines for allergen immunotherapy trials We caution that our study reports only the safety
recommend that the combined symptommedication score data from RCTs, and is not a comprehensive review of
be used as the primary outcome measure.72 Few studies the prevalence of adverse events, which would require
or reviews have reported this outcome measure. the review of nonrandomized studies and case reports.
When evaluating the magnitude of effect for indi- Additional RCTs are needed to strengthen the evidence
vidual studies, there is no consensus on what is a clini- for the efficacy and safety of SCIT. Future studies
cally relevant improvement in a measured outcome. The should use standardized methods to report primary clini-
World Allergy Organization taskforce recommends that cal outcome measures, adverse events, allergen doses,
the minimal clinically relevant efficacy should be at dosing frequency, and treatment duration as well as a
least 20% higher than placebo.72 Although the taskforce uniform method of assessing clinical efficacy, as recom-
refers to placebo-controlled studies, our review included mended in published guidelines for allergen immuno-
studies comparing SCIT to pharmacotherapy; for these therapy trials.7274 Future studies should have clear
studies, we would expect a smaller difference. Hence, we concealment of allocation and masking of the interven-
considered that a 15% improvement indicates a moder- tion throughout the study to reduce bias. Given increas-
ate magnitude of effect for the purposes of clinical deci- ing discussion in the scientific community on the clinical
sion making; <15% is weak. use and efficacy of single-allergen versus multiple-
Most of the included trials used a single allergen allergen regimens, additional studies with head-to-head
for immunotherapy; hence, it is difficult to determine comparisons of single-allergen versus multiple-allergen
the extent to which this evidence applies to multiple- regimens are needed. Reporting results by asthma sever-
allergen regimens, which are commonly used in the ity would be useful for assessing whether there is a sub-
United States. Enrolled participants in these studies group of patients with asthma that may particularly
had mild or moderate asthma; the generalizability of benefit from immunotherapy.
these findings for patients with more severe asthma is When applying the results of this systematic review
uncertain. to clinical practice, the risk/benefit ratio of SCIT must be
We acknowledge limitations posed by these data. A kept in mind. Although our study was limited to the
meta-analysis was not performed due to substantial het- safety data of RCTs, a recent update on the safety of spe-
erogeneity of the included studies. There was extreme cific immunotherapy75 reviewed the previous literature
variability in outcomes reported, scoring of primary out- and found the likelihood of fatalities from SCIT to be one
comes, allergen dosing, treatment schedules, and meth- in 22.5 million doses, and 17 fatalities occurred from
ods of reporting safety data. Additionally, relevant 1990 to 2001. The risk of death from SCIT, although very
statistical information on precision was frequently rare, must be taken in consideration when reviewing
unavailable; therefore, the data could not be pooled to treatment recommendations and shared with patients.
perform a meta-analysis. Our grading system was uti- The decision to start SCIT should be made on a case-by-
lized to overcome these obstacles. case basis, looking at the potential improvement in
We included only RCTs in this review, and yet the symptoms and the risks involved.
studies varied substantially in their risks of bias.
Although all studies used randomization, several stud-
ies did not specify whether allocation schemes were CONCLUSION
concealed, or if the type of intervention was concealed We found moderate to strong evidence to support
from the participants and outcomes assessors. Half of the effectiveness of SCIT for treatment of allergic

Laryngoscope 124: March 2014 Erekosima et al.: Subcutaneous Immunotherapy Systematic Review
625
rhinoconjunctivitis and asthma, particularly using 17. Reid MJ, Moss RB, Hsu YP, Kwasnicki JM, Commerford TM, Nelson BL.
Seasonal asthma in northern California: allergic causes and efficacy of
single-allergen immunotherapy regimens. Adverse reac- immunotherapy. J Allergy Clin Immunol 1986;78(4 pt 1):590600.
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gen immunotherapy is accompanied by selective persistence of blocking
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