Ann Allergy Asthma Immunol xxx (2016) 1e9

Contents lists available at ScienceDirect

Effect of acupuncture on house dust mite specic IgE, substance

P, and symptoms in persistent allergic rhinitis
John Leslie McDonald, PhD *; Peter K. Smith, PhD *; Caroline A. Smith, PhD y; Charlie Changli Xue, PhD z;
Brenda Golianu, MD x; Allan W. Cripps, PhD *; the Mucosal Immunology Research Group
* School

of Medicine, Menzies Health Institute, Grifth University, Queensland, Australia

National Institute of Complementary Medicine, Western Sydney University, Sydney, Australia
z
Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Victoria, Australia
x
Stanford University, Palo Alto, California
y

A R T I C L E

I N F O

Article history:
Received for publication October 29, 2015.
Received in revised form March 31, 2016.
Accepted for publication April 5, 2016.

A B S T R A C T

Background: Clinical evidence suggests that acupuncture improves symptoms in persistent allergic rhinitis,
but the physiologic basis of these improvements is not well understood.
Objective: A randomized, sham-controlled trial of acupuncture for persistent allergic rhinitis in adults
investigated possible modulation of mucosal immune responses.
Methods: A total of 151 individuals were randomized into real and sham acupuncture groups (who received
twice-weekly treatments for 8 weeks) and a no acupuncture group. Various cytokines, neurotrophins,
proinammatory neuropeptides, and immunoglobulins were measured in saliva or plasma from baseline to
4-week follow-up.
Results: Statistically signicant reduction in allergen specic IgE for house dust mite was seen only in the
real acupuncture group, from 18.87 kU/L (95% CI, 10.16e27.58 kU/L) to 17.82 kU/L (95% CI, 9.81e25.83 kU/L)
(P .04). A mean (SE) statistically signicant down-regulation was also seen in proinammatory neuropeptide substance P (SP) 18 to 24 hours after the rst treatment from 408.74 (299.12) pg/mL to 90.77 (22.54)
pg/mL (P .04). No signicant changes were seen in the other neuropeptides, neurotrophins, or cytokines
tested. Nasal obstruction, nasal itch, sneezing, runny nose, eye itch, and unrefreshed sleep improved
signicantly in the real acupuncture group (postnasal drip and sinus pain did not) and continued to improve
up to 4-week follow-up.
Conclusion: Acupuncture modulated mucosal immune response in the upper airway in adults with
persistent allergic rhinitis. This modulation appears to be associated with down-regulation of allergen
specic IgE for house dust mite, which this study is the rst to report. Improvements in nasal itch, eye
itch, and sneezing after acupuncture are suggestive of down-regulation of transient receptor potential
vanilloid 1.
Trial Registration: Australian New Zealand Clinical Trials Registry Identier: ACTRN 12610001052022.
2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Introduction
The pathogenesis of allergic rhinitis involves a complex crosstalk among cytokines, neurotrophins, and proinammatory neuropeptides.1 Acupuncture has been found to improve symptoms
and quality of life in patients with allergic rhinitis, and there is
Reprints: John Leslie McDonald, PhD, Menzies Health Institute, Grifth University,
Queensland 4222, Australia; E-mail: [email protected].
Disclosures: Authors have nothing to disclose.
Funding Sources: Funding for this study was provided by grant 536564
(2009e2011) from the National Health and Medical Research Council.
Group Information: The members of the Mucosal Immunology Research Group are
Nicholas West, PhD, Ibtisam Ghazawi, PhD, Pauline Low, PhD, and Ann-Christen
Bischoff.

evidence that acupuncture may modulate some biomarkers.2

Although down-regulation of substance P (SP), vasoactive intestinal peptide (VIP), and total IgE after acupuncture has been previously reported, no studies to date have investigated potential
modulation of the neurotrophins nerve growth factor (NGF) and
brain-derived neurotrophic factor (BDNF).2,3 We hypothesize that
acupuncture may down-regulate neurotrophins, proinammatory
neuropeptides, and IgE and shift TH1/TH2 balance away from TH2
dominance, while simultaneously reducing nasal mucosal inammation and hypersensitivity.4 To test this hypothesis, a randomized,
sham-controlled trial of acupuncture treatment for persistent
allergic rhinitis was undertaken in which cytokines, neurotrophins,
proinammatory neuropeptides, IgE, nasal airway clearance,
symptoms, and quality of life were measured.

http://dx.doi.org/10.1016/j.anai.2016.04.002
1081-1206/ 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

J.L. McDonald et al. / Ann Allergy Asthma Immunol xxx (2016) 1e9

Methods
Trial Design, Ethics Approval, and Trial Registration
The study was a 3-arm, participant- and assessor-masked, parallel, randomized, sham-controlled trial. Initial screening, recruitment, and follow-up phases were conducted at a private allergy
clinic at Southport, Queensland, in weeks 0, 9, and 12 (Fig 1).
Acupuncture treatment was administered at a private acupuncture
clinic also in Southport, twice weekly for 8 weeks (weeks 1 to 8).
Ethical clearance for the study was obtained from the Grifth
University Human Research Ethics Committee. The study was
registered with the Australian New Zealand Clinical Trials Registry
(Australian New Zealand Clinical Trials Registry Identier: ACTRN
12610001052022).
Inclusion and Exclusion Criteria
The inclusion criteria for the study were as follows: men and
women aged 18 to 45 years, a more than 2-year history of moderate
to severe allergic rhinitis, positive skin prick test result to 3 clinically relevant local grass pollens (Bahia grass, Johnson grass, and
Bermuda grass) and/or house dust mite (Dermatophagoides pteronyssinus), and positive radioallergosorbent test result to house
dust mite or Bermuda grass. The exclusion criteria for the study
were as follows: noneallergic rhinitis, negative skin prick test
result to 3 local grass pollens and/or house dust mite and negative
blood test result to house dust mite or Bermuda grass, acupuncture
treatment for allergic rhinitis or specic immunotherapy in the
previous 2 years, respiratory diseases (eg, asthma, nasal polyposis,
and chronic obstructive pulmonary disease), infectious diseases,
medications that affect salivary ow and components (eg, systemic
corticosteroids, diuretics, and some antidepressants), pregnancy,
and nasal recreational drugs.
Recruitment and Randomization Procedures
Participants were recruited through public media and e-mails to
Grifth University students and staff. A total of 152 participants
were screened (Fig 2). Participants were randomized to 1 of the 3

Week 0
Allergy clinic
Screening,
recruitment
randomizaon
SPT, PNIF,
MITO,
iTNSS,
Mini-RQLQ
Saliva
samples:
SP, VIP, ECP
QML
Blood
samples:
RAST, IgE,
CGRP, NGF,
BDNF, IL-2,
IL-4, IL-10,
IL-12 (p70),
IFN-, eotaxin

Week 1

Week 2

Week 3

Weeks
4 and 5

study groups: real acupuncture, sham acupuncture, or no

acupuncture. The randomization schedule was generated using the
Research Randomizer tool (http://www.randomizer.org), and on
enrollment, each participant was allocated to the next available line
on the schedule. Recruitment was conducted in Southport,
Queensland, between October 2009 and May 2012, and the trial
was completed in August 2012.
Masking
Participants in the real acupuncture and sham acupuncture
groups were masked to group allocation, and this masking was
later conrmed to have been successful by the exit debrief questionnaire results. Staff at the allergy clinic who performed clinical
assessments and laboratory staff who performed tests on saliva and
blood were masked to group allocations. Data entry and statistical
analysis were also performed with masking of group allocations.
Sample Size Calculation
A power analysis was performed using Sample Power (IBM SPSS,
Dublin, Ireland). A sample size of 36 for each group was predicted to
provide 80% power with a type 1 error rate of 5% (2-tailed).
Outcome Measures
The primary outcome for the study was any modulation in
mucosal immune response in the upper respiratory tract after
acupuncture treatment. Measurements included total and allergen
specic IgE, proinammatory neuropeptides, neurotrophins, and
cytokines. The secondary outcome was to measure changes in
symptoms, quality of life, and nasal airway clearance.
Saliva Collection
Samples of mixed saliva were collected using cotton cellulose
eye-spears as previously described.5 After collection, the samples
were placed immediately in a 18 C freezer and transported to the
laboratory, where the samples were frozen in liquid nitrogen and
stored at 70 C until further processed. When the sample was

Week 6

Acupuncture clinic

Weeks
7 and 8

Week 9

Weeks
10 and
11

Week 12

Allergy clinic

Allergy clinic

PNIF, MITO,
iTNSS,
MiniRQLQ

PNIF, MITO,
iTNSS,
MiniRQLQ

2 Acupuncture treatments per week

Saliva
samples:
SP, VIP

Saliva
samples:
SP, VIP

Saliva
Saliva
Exit
samples:
samples:
debrief
SP, VIP
SP, VIP
Daily symptom and medicaon dairy

Saliva
samples:
SP, VIP, ECP
QML
Blood
samples:
RAST, IgE,
CGRP, NGF,
BDNF, IL-2,
IL-4, IL-10,
IL-12 (p70),
IFN-, eotaxin

Figure 1. Trial design. BDNF indicates brain-derived neurotrophic factor; CGRP, calcitonin geneerelated peptide; ECP, eosinophilic cationic protein; IL, interleukin; IFN-g,
interferon g; iTNSS, instantaneous total nasal symptom score; Mini-RQLQ, Mini Rhinoconjunctivitis Quality of Life Questionnaire; MITO, mean inferior turbinate obstruction;
NGF, nerve growth factor; PNIF, peak nasal inspiratory ow; QML, Queensland Medical Laboratories; RAST, radioallergoabsorbent test; SP, substance P; SPT, skin prick test; VIP,
vasoactive intestinal peptide.

J.L. McDonald et al. / Ann Allergy Asthma Immunol xxx (2016) 1e9

Incomplete
screening

Screened

Ineligible

152

Randomized

Re-enrolled

142

Commenced
treatment

151
Real
acupuncture

No
acupuncture

49

50
Sham
acupuncture

Withdrawn

Excluded

12

Withdrawn

52

13

Withdrawn

Excluded

13

Completed

36

Completed
Completed

37

37
Figure 2. Participant owchart.

thawed, it was centrifuged at 4 C at 1,000g to recover the saliva and

used for analysis or refrozen in 0.5-mL aliquots for further analysis.
Blood Collection
Blood collection was performed by the commercial pathology
company Queensland Medical Laboratories (Queensland,
Australia). A 12.5-mL blood sample was collected by venupuncture
into a plain and heparinized tube. Serum and plasma samples were
frozen at 70 C in 0.5-mL aliquots until required for analysis.
Laboratory Analysis
Laboratory analysis (apart from immunoglobulin testing) was
performed by Grifth University laboratory staff who were masked
to participants group allocations. All assays were performed with
neat saliva or plasma/serum except for the BDNF plasma assay,
which used a 1:20 dilution.
Total and Specic Antibodies
Total IgE and allergen specic IgE antibodies to house dust mite,
Bermuda grass, Johnson grass (Sorghum halepense), and Bahia grass
(Paspalum notatum) were measured in serum by ImmunoCAP

(Phadia, Uppsala, Sweden). All immunoglobulin testing was performed by Queensland Medical Laboratories. Enzyme-linked
immunosorbent assays were conducted following the manufacturers instructions on cytokines, neuropeptides, neurotrophins,
and eosinophilic cationic protein (ECP).
Cytokines
Cytokines indicative of a TH1 response (interferon g [IFN-g],
interleukin [IL] 12), a TH2 response (IL-4), and proinammatory
cytokines (IL-2 and eotaxin) and IL-10 in plasma were assayed with
a EMD Millipore Human Cytokine/Chemokine Magnetic Bead Panel
HCYTOMAG-60K-06 (EMD Millipore, Billerica, Massachusetts).
Neuropeptides and Neurotrophins
Neurotrophins and neuropeptides were assayed with the
following commercial kits: HNP-35K-01 (EMD Millipore) for SP,
E90380Hu (USCN Life Science Inc, Wuhan, Hubei, Peoples Republic
of China) for VIP, E90876Hu (USCN Life Science Inc) for calcitonin
geneerelated peptide (CGRP), human adipokine kit HADK2-61KBO1 (EMD Millipore) for NGF, and Chemikine BDNF Sandwich
enzyme-linked immunosorbent assay CYT306 (EMD Millipore) for
BDNF.

J.L. McDonald et al. / Ann Allergy Asthma Immunol xxx (2016) 1e9

Eosinophilic Cationic Protein

ECP was assayed in saliva using Mesacup 7618E supplied by
Medical and Biological Laboratories International (Woburn,
Massachusetts).
Instantaneous Total Nasal Symptom Score
Participants were scored on a scale from 0 (not at all) to 3 (severe) on 4 symptoms at the allergy clinic at week 0 (on recruitment), week 9 (1-week follow-up after treatment), and week 12
(4-week follow-up after treatment). The 4 symptoms were runny
nose, itchy nose, stuffy nose, and sneezing.
Mini-Rhinoconjunctivitis Quality of Life Questionnaire
Participants completed the Mini-Rhinoconjunctivitis Quality of
Life Questionnaire (Mini-RQLQ) at the allergy clinic in weeks 0, 9,
and 12. The Mini-RQLQ contains 14 items scored on a scale of
severity from 0 (not affected) to 6 (extremely affected): regular
activities, recreational activities, sleep, need to rub nose or eyes,
need to blow nose repeatedly, sneezing, stuffy or blocked nose,
runny nose, itchy eyes, sore eyes, watery eyes, tiredness and/or
fatigue, thirst, and feeling irritable. The 14 items were divided into 5
domains: activity score, practical problems score, nasal symptoms
score, eye symptoms score, and other symptoms score.
Daily Symptom and Medication Diary
Participants completed a daily symptom and medication diary
from week 1 to week 12. The presence or absence of 7 symptoms
was recorded daily: nasal itch, eye itch, sneezing, runny nose,
postnasal drip, unrefreshed sleep, and sinus pain. Weekly symptom
scores were calculated from a total of 49 (7 symptoms for 7 days).
All medications taken during the trial were also recorded daily,
yielding a weekly score of a total of 7.
Mean Inferior Turbinate Obstruction
Mean (between left and right) inferior turbinate obstruction
(MITO) scores (expressed as a percentage of the nasal airway space)
were measured with visual inspection by the allergologist in weeks
0, 9, and 12.
Peak Nasal Inspiratory Flow
Peak nasal inspiratory ow (PNIF) was measured by the clinical
assistant at the allergy clinic using anterior active rhinomanometry
according to the International Committee for the Standardization of
Rhinomanometry guidelines.6,7 The PNIF was measured at weeks 0,
9, and 12.
Real Acupuncture Treatment
Acupuncture point selection
The rationale for acupuncture point selection in this study was
based on 3 sources of data: points frequently used in research
studies, points frequently recommended in modern acupuncture
textbooks in the clinical sections, and nally points for which indications relevant to allergic rhinitis frequently appear in the point
indications sections of modern texts.8e23 The following points were
chosen for this study: Yintang, LI 20, LI 4, ST 36, and GV 23. All
points were located according to the World Health Organization
International Standard Acupuncture Point Locations in the Western
Pacic Region.24
Duration and Frequency of Acupuncture Treatment
A review of previous studies on acupuncture for allergic rhinitis
indicated that a treatment regimen of twice-weekly treatments for
6 to 8 weeks produced signicantly superior clinical outcomes

when compared with studies that used shorter or less frequent

treatments.8e14,25e27 Therefore, treatments were given twice
weekly for 8 weeks, with a 2- to 4-day break between treatments.
Needle Technique
Traditional Chinese-style single-use disposable stainless steel
needles (0.25  40 mm) (C and G acupuncture needles; Helio
Supply Co Pty Ltd, Sydney, Australia) were used. The needles were
inserted at the indicated points but not manipulated. Yintang, LI 20,
and GV 23 were needled obliquely to a depth of 3 to 5 mm, whereas
LI 4 and ST 36 were needled perpendicularly to a depth of 10 to 15
mm. Needles were retained for 20 minutes (without manipulation)
and then removed.
Time of Treatment
To reduce the inuence of circadian variations, all acupuncture
treatments were performed between 6 AM and midday, twice
weekly.
Sham Acupuncture Treatment
Nonechannel points used in sham acupuncture protocols have
been shown not to be inert28,29; however, because there is no sham
acupuncture protocol that has been validated as inert,30,31 needling
nonechannel points was the most appropriate invasive sham
protocol available.
Acupuncture point selection
For the sham acupuncture group, 4 sites (needled bilaterally)
were selected, which did not correspond to the locations of known
acupuncture points and did not lie on identied acupuncture
channels (meridians). Midline points on the head were avoided
because this would lie on an identied acupuncture channel, the
governor vessel (Dumai). The acupuncture points were as follows:
forehead sham point: 1 cun lateral to GB 14 (Yangbai); cheek sham
point: the midpoint of the line between LI 20 and SI 19 (Tinggong);
hand sham point: on the dorsum of the hand, at the midpoint of the
second metacarpal bone on the ulnar side of the bone; and leg
sham point: on the lateral aspect of the lower leg, 1 cun below the
point Linghou (M-LE-24). The forehead sham point was needled
obliquely, whereas the cheek sham was needled perpendicularly,
both to a depth of 2 to 3 mm. Hand and leg sham points were
needled perpendicularly to a depth of 5 to 10 mm and 10 to 15 mm,
respectively.
Other treatment parameters
The frequency and duration of sham acupuncture treatment
were the same as the real acupuncture group, as was the needle
technique and timing of treatment. All acupuncture treatments
were given by an acupuncturist (J.L.M.) who has bachelor of health
science (acupuncture) and master of acupuncture degrees and
more than 35 years of clinical experience as an acupuncturist,
including decades of experience in treating allergic rhinitis.
Cointerventions
All participants were permitted to use nonsteroidal oral relief
medications throughout the trial, which they recorded in a daily
symptom and medication diary.
Statistical Analysis
All values from laboratory analysis were standardized across
plates (using mean ratios of all available duplicate tests) before
statistical analysis. All data were tested for normality with the
Kolmogorov-Smirnov and Shapiro-Wilk tests. Nonnormal data
were log transformed and then retested for normality. To compare
time points within groups, paired-sample t tests were used

J.L. McDonald et al. / Ann Allergy Asthma Immunol xxx (2016) 1e9

whenever data (natural or logged) were normal or the Friedman

test for data which were not normally distributed. Between-group
analyses were conducted using independent-sample t tests for
normally distributed data and independent-sample Kruskal-Wallis
tests for nonparametric data. Correlation analyses were conducted
using the Spearman r. Statistical calculations were conducted using
SPSS statistical software for Windows, version 21 (SPSS Inc, Chicago, Illinois). Missing values and outliers for biomarkers (values
lying outside the published upper and lower detection limits for
each biomarker) were excluded from all analyses. Missing values in
measures for symptoms, quality of life, and nasal airway clearance
for the 110 participants who completed the study were imputed
using last datum carried forward. Valid multivariate analysis of
variance tests could not be performed because normality tests and
multivariate tests failed for most of the data.
Results
Baseline Characteristics
There were no statistically signicant differences between
groups at baseline in sex, age, total IgE, allergen specic IgE, NGF,
BDNF, SP, VIP, CGRP, ECP, eotaxin, symptom severity, PNIF or MITO.
However, there were some signicant between-group differences
in IL-2, IL-4, IL-10, IL-12 (p70), and IFN-g, with the no acupuncture
group having signicantly higher levels of these cytokines than the
sham acupuncture group. Because these cytokines had no signicant changes after treatment, these baseline differences are unlikely to have had any effect on the results of the study.

Cytokines
Cytokines indicative of a TH1 response (IFN-g, IL-12), a TH2
response (IL-4), and proinammatory cytokines (IL-2 and eotaxin)
and IL-10 were measured, but there were no signicant differences
in any cytokine between week 0 and week 12 in any group.
Neuropeptides and Neurotrophins
In the real acupuncture group, there were signicant decreases
in salivary SP between week 1 before treatment and 18 to 24 hours
after treatment in both week 1 (P .04) and week 3 (P .04)
(Table 2). In the sham acupuncture group, there were signicant
decreases in SP between week 1 before treatment and week 6 (18 to
24 hours after treatment) (P .03). There were no signicant differences between time points in the no acupuncture group. There
were signicant differences between the real acupuncture and no
acupuncture groups at week 3 (P .002) and week 6 (P .02) and
between sham acupuncture and no acupuncture at week 3 (P .03)
and week 6 (P .003). There were no signicant differences between groups at week 12 and no signicant differences between
the real and sham acupuncture groups at any time point.
Salivary VIP levels were signicantly lower in the real
acupuncture group compared with the sham acupuncture group at
week 1 (18e24 hours after treatment) (P .04); however, there
were no signicant differences between time points in any group.
There were no signicant differences in CGRP, NGF, or BDNF
between week 0 and week 12 in any group. This is the rst study, to
our knowledge, to examine NGF and BDNF after acupuncture for
allergic rhinitis.

Primary Outcomes
Total and specic antibodies
There were signicant mean (95% CI) decreases in total serum
IgE between week 0 and week 12 from 217.56 (60.27, 374.86) kU/L
to 191.91 (53.58, 330.23) kU/L (P .02) in the real acupuncture
group and from 299.31 (165.40, 433.23) to 269.46 (153.32, 385.60)
kU/L (P .02) in the sham acupuncture group but no signicant
difference in the no acupuncture group (Table 1). There were no
signicant differences between groups at week 0 or week 12.
A statistically signicant mean (95% CI) reduction was found in
serum allergen specic IgE for house dust mite at week 12
(compared with week 0) after real acupuncture from 18.87 (10.16,
27.58) kU/L to 17.82 (9.81, 25.83) kU/L (P .04). No signicant
differences were seen after sham acupuncture or no acupuncture
(Table 1). No differences were seen between week 0 and week 12 in
3 regional grass pollens (Bahia grass, Johnson grass, and Bermuda
grass) for any of the groups with only one exception. In the no
acupuncture group, there was an unexplained statistically signicant reduction in allergen specic IgE for Bahia grass between week
0 and week 12 (P .01).
Table 1
Total IgE and Allergen Specic IgE for House Dust Mite In Serum: Time Point
Comparisons Within Groups
Group

Mean (95% CI)

Total IgE, kU/L

No acupuncture (n 34)
Week 0
Week 12
Sham acupuncture (n 35)
Week 0
Week 12
Real acupuncture (n 32)
Week 0
Week 12
a

House dust mite IgE, kU/L

337.71 (145.95, 529.46)

306.15 (139.02, 473.27)

29.98 (18.14, 41.81)

29.61 (17.83, 41.39)

299.31 (165.40, 433.23)

269.46 (153.32, 385.60)a

31.22 (20.00, 42.44)

29.94 (19.36, 40.53)

217.56 (60.27, 374.86)

191.91 (53.58, 330.23)a

18.87 (10.16, 27.58)

17.82 (9.81, 25.83)a

P < .05 compared with week 0.

Secondary Outcomes
Instantaneous total nasal symptom score
Within the real acupuncture group, there was a signicant
reduction in instantaneous total nasal symptom score (iTNSS) between week 0 and week 9 (28.2%; P .01) and between week 0 and
week 12 (34.3%; P .003) (Table 3). No signicant differences were
seen between time points within the sham and no acupuncture
Table 2
Substance P in Saliva: Time Point Comparisons Within Groups
Group

No acupuncture
Week 1 (n 37)
Week 3 (n 37)
Week 6 (n 37)
Week 12 (n 37)
Sham acupuncture
Week 1 pre (n 36)
Week 1 (18e24 hours)
(n 36)
Week 3 (18e24 hours)
(n 33)
Week 6 (18e24 hours)
(n 34)
Week 12 (n 36)
Real acupuncture
Week 1 pre (n 36)
Week 1 (18e24 hours)
(n 34)
Week 3 (18e24 hours)
(n 33)
Week 6 (18e24 hours)
(n 33)
Week 12 (n 36)
a

Mean
(SE), pg/mL

Logged
Logged mean P value
mean (SE), (SE) difference (2-tailed)
pg/mL
from week
1 before
treatment

428.26
383.24
464.31
491.03

2.05
2.02
2.02
1.95

(112.13)
(94.21)
(144.79)
(252.04)

(0.15)
(0.14)
(0.14)
(0.15)

0.03 (0.08)
0.03 (0.67)
0.06 (0.54)

.69
.49
.42

413.37 (299.50) 1.69 (0.14)

536.80 (337.65) 1.40 (0.16)

0.29 (0.17)

.10

603.60 (362.52) 1.53 (0.18)

0.10 (0.16)

.52

401.16 (317.78) 1.41 (0.16)

0.33 (0.14)

.03a

742.14 (416.16) 1.76 (0.17) 0.07 (0.16)

.68

408.74 (299.12) 1.75 (0.14)

90.77 (22.54) 1.57 (0.12)

0.24 (0.11)

.04a

74.19 (16.84)

1.40 (0.14)

0.34 (0.16)

.04a

110.42 (29.94)

1.57 (0.13)

0.20 (0.18)

.26

240.72 (114.86) 1.64 (0.14)

0.11 (0.16)

.48

P < .05 compared with week 1 before treatment.

J.L. McDonald et al. / Ann Allergy Asthma Immunol xxx (2016) 1e9

Table 3
Mini Rhinoconjunctivitis Quality of Life Questionnaire (Mini-RQLQ) Total Scores
Week

0
9
12
a

No acupuncture
(n 37)

Sham acupuncture
(n 37)

Real acupuncture
(n 36)

Mean (SE)

SD

Mean (SE)

SD

Mean (SE)

SD

43.62 (2.58)
44.43 (1.95)
40.78 (2.72)

15.69
11.88
16.52

46.89 (2.11)
34.51 (3.01)a
38.73 (3.17)b

12.86
18.32
19.25

44.33 (2.72)
34.06 (3.12)a
30.72 (2.93)a

16.31
18.72
17.59

P < .001 compared with week 0.

P < .05 compared with week 0.

groups. There were no signicant between-group differences at any

time point.
Mini-Rhinoconjunctivitis Quality of Life Questionnaire
There were signicant reductions in total Mini-RQLQ scores
between week 0 and week 9 in the real acupuncture group (23.2%;
P .001) and the sham acupuncture group (26.4%; P .001). There
were also signicant reductions between week 0 and week 12 in
the real acupuncture group (30.7%; P .001) and the sham
acupuncture group (17.4%; P .007) (Table 3). There were signicant differences between the no acupuncture group and both the
real acupuncture (P .006) and the sham acupuncture (P .007)
groups at week 9 and between the no acupuncture and real
acupuncture groups at week 12 (P .01). Although there is no
signicant difference between the real and sham acupuncture
groups in Mini-RQLQ scores at week 9, there is a consistent pattern
in total scores and across all 5 domains, which reveals continued
improvement in the real acupuncture group between week 9 and
week 12 but deterioration in the sham acupuncture group.
Daily symptom and medication diary
Of the 110 participants who completed the study, 88 submitted
their daily symptom and medication diaries. In the real acupuncture group, there were signicant differences between total weekly
symptom scores for week 1 and week 3 (P .02), and these differences persisted every week until week 12 (Table 4). The percentage improvement in daily symptom diary scores from week 1
to week 12 was 24.4%. There were no signicant differences between week 1 and any other week in the other groups. When the 7
symptoms included in the daily symptom diary were examined
separately, 5 symptoms improved signicantly in the real
acupuncture group (nasal itch, eye itch, sneezing, runny nose, and
unrefreshed sleep), whereas 2 symptoms did not improve (postnasal drip and sinus pain) (Table 5). In the sham acupuncture group,
the only symptom that improved signicantly was unrefreshed
sleep. There were no changes in the no acupuncture group. After
real acupuncture, the percentage improvement from week 1 to

week 12 and the maximal improvement in any week compared

with week 1, respectively, were 47.5% and 47.5% for unrefreshed
sleep, 23.3% and 35.0% for nasal itch, 20.6% and 33.0% for sneezing,
16.7% and 28.6% for runny nose, and 16.1% and 27.3% for eye itch.
Mean inferior turbinate obstruction
There were no signicant differences within any group between
time points. The only signicant between-group difference was
between the no acupuncture and sham acupuncture groups at
week 9 (P .02).
Peak nasal inspiratory ow
There were no signicant differences between groups at any
time point. There were no signicant differences in any group between week 0 and week 9 or between week 0 and week 12, except
for a signicant difference between week 0 and week 12 in the no
acupuncture group (P .02).
Safety
There were no serious adverse events reported or observed
during the study. There were 40 minor adverse events during the
study: slight bruising (n 27), acute transitory pain on needle
insertion (n 8), acute transitory pain and pins and needles
sensation on insertion (n 1), soreness (n 1), soreness and
itching (n 1), swelling (n 1), and tingling (n 1). Because
approximately 1,300 acupuncture treatments were administered
during the study, this represents a minor adverse events rate of
approximately 3%.
Discussion
Four weeks after 16 sessions of real acupuncture treatment
twice weekly, total IgE decreased signicantly (P .02), whereas
allergen specic IgE for house dust mite also decreased signicantly
(P .04). One previous study on acupuncture for persistent allergic
rhinitis reported a posttreatment signicant decrease in total IgE (P
< .01).27 This was the rst study to report a signicant decrease in
allergen specic IgE for house dust mite in adults with persistent
allergic rhinitis. These ndings suggest that acupuncture modulates
the allergic immune response through down-regulation of allergen
specic IgE for house dust mite possibly through the reduction of
TH2 dominance.32
What About VIP?
Down-regulation of proinammatory neuropeptide SP in saliva
after acupuncture for persistent allergic rhinitis has been previously reported.3 However, the course of the down-regulation of SP
in this study was of particular interest because it did not correlate
to the course of symptomatic improvements (Fig 3). The rst time

Table 4
Daily Symptom Diary Mean Weekly Total Scores
Week

1
2
3
4
5
6
7
8
9
10
11
12
a

No acupuncture (n 27)

Real acupuncture (n 30)

SD

Mean (SE)

SD

Mean (SE)

SD

P value

19.19
19.00
18.63
18.85
19.70
18.67
19.11
17.44
17.44
18.37
19.11
18.96

12.40
14.12
14.24
13.47
14.44
13.72
13.60
13.90
14.34
13.70
15.00
15.83

19.03
19.52
18.81
16.61
16.23
14.61
17.03
15.42
15.32
15.45
15.42
15.29

10.65
10.53
10.53
12.37
12.65
12.41
11.97
9.73
11.20
11.29
12.33
11.66

23.27
21.73
20.33
18.97
18.13
17.63
18.70
18.07
18.63
18.50
18.10
17.60

14.67
15.81
16.34
17.20
17.54
17.15
17.15
17.20
17.64
17.60
17.76
18.46

.
.
.02a
.007a
.001b
.001b
.003a
.001b
.009a
.01a
.004a
.003a

(2.39)
(2.72)
(2.74)
(2.59)
(2.78)
(2.64)
(2.62)
(2.68)
(2.78)
(2.64)
(2.89)
(3.05)

P < .05 compared with week 1.

P < .001 compared with week 1.

Sham acupuncture (n 31)

Mean (SE)

(1.91)
(1.89)
(1.89)
(2.22)
(2.27)
(2.23)
(2.15)
(1.75)
(2.01)
(2.02)
(2.21)
(2.09)

(2.68)
(2.89)
(2.98)
(3.14)
(3.20)
(3.13)
(3.13)
(3.14)
(3.22)
(3.21)
(3.24)
(3.37)

Salivary substance P in pg/mL (10)

vs weekly mean symptom scores

.36
.11
.003a
.004a
.01a
.02a
.002a
.04a
.02a
.004a
.002a
(0.22)
(0.36)
(0.38)
(0.42)
(0.44)
(0.47)
(0.48)
(0.43)
(0.50)
(0.50)
(0.52)
0.20
0.60
1.23
1.30
1.20
1.17
1.67
0.93
1.23
1.53
1.77
(0.54)
(0.54)
(0.56)
(0.55)
(0.57)
(0.56)
(0.53)
(0.57)
(0.56)
(0.53)
(0.56)
(0.57)
3.73
3.53
3.13
2.50
2.43
2.53
2.57
2.07
2.80
2.50
2.20
1.97

Mean (SE)
difference
from week 1
Mean (SE)

Unrefreshed sleep

P value

J.L. McDonald et al. / Ann Allergy Asthma Immunol xxx (2016) 1e9
45
40
35
30
25
20
15
10
5
0
Week 1

Week 3

Week 6

Week 12

Daily symptom diary weekly means

3.30
2.77
3.20
2.97
2.90
2.53
2.40
2.47
2.57
2.67
2.77
2.40

(0.53)
(0.54)
(0.53)
(0.56)
(0.57)
(0.53)
(0.52)
(0.57)
(0.53)
(0.52)
(0.55)
(0.57)

0.53
0.10
0.33
0.40
0.77
0.90
0.83
0.73
0.63
0.53
0.53

(0.22)
(0.30)
(0.38)
(0.36)
(0.26)
(0.32)
(0.27)
(0.30)
(0.35)
(0.31)
(0.22)

.02a
.75
.39
.28
.006a
.008a
.006a
.02a
.08
.10
.008a

4.03
3.73
2.93
3.00
2.70
3.03
3.43
3.33
3.00
3.03
3.60
3.20

(0.49)
(0.50)
(0.50)
(0.53)
(0.51)
(0.48)
(0.50)
(0.49)
(0.51)
(0.48)
(0.53)
(0.58)

0.30
1.10
1.03
1.33
1.00
0.60
0.70
1.03
1.00
0.43
0.83

(0.35)
(0.43)
(0.34)
(0.38)
(0.38)
(0.41)
(0.37)
(0.44)
(0.43)
(0.47)
(0.58)

.39
.02a
.005a
.002a
.01a
.15
.07
.02a
.03a
.37a
.16

3.60
3.57
3.23
2.90
2.57
2.90
2.87
3.00
2.93
3.00
2.93
3.00

(0.55)
(0.54)
(0.51)
(0.52)
(0.53)
(0.52)
(0.56)
(0.56)
(0.57)
(0.54)
(0.55)
(0.58)

0.03
0.37
0.70
1.03
0.70
0.73
0.60
0.67
0.60
0.67
0.60

(0.36)
(0.36)
(0.43)
(0.40)
(0.47)
(0.44)
(0.52)
(0.51)
(0.47)
(0.47)
(0.44)

.93
.32
.11
.01a
.15
.11
.26
.20
.22
.17
.18

Figure 3. Changes in substance P vs changes in symptoms.

P < .05 compared with week 1.

P < .001 compared with week 1.

.21
.27
.30
.12
<.001b
.11
.006a
.02a
.03a
.009a
.03a
(0.24)
(0.38)
(0.41)
(0.39)
(0.33)
(0.36)
(0.32)
(0.37)
(0.41)
(0.39)
(0.42)
0.30
0.43
0.43
0.63
1.40
0.60
0.93
0.90
0.97
1.07
0.93
(0.47)
(0.55)
(0.57)
(0.58)
(0.55)
(0.52)
(0.54)
(0.53)
(0.54)
(0.54)
(0.54)
(0.59)
4.00
3.70
3.57
3.57
3.37
2.60
3.40
3.07
3.10
3.03
2.93
3.07

Mean (SE)
difference from
week 1
Week

1
2
3
4
5
6
7
8
9
10
11
12

Mean (SE)
Mean (SE)
Mean (SE)
Mean (SE)

P value

Eye itch
Nasal itch

Mean (SE)
difference
from week 1

P value

Sneezing

Mean (SE)
difference
from week 1

P value

Runny nose

Mean (SE)
difference
from week 1

P value

Substance P

Table 5
Daily Symptom Diary Weekly Means for the Real Acupuncture Group (n 30)

point at which SP signicantly decreased was 18 to 24 hours after

the rst acupuncture treatment in week 1, from a mean (SE) of
408.74 (299.12) pg/mL to 90.77 (22.54) pg/mL (P .04); however,
the rst signicant decrease in weekly symptom score was not seen
until week 3 (Table 2 and Table 6). SP reached its lowest point in
week 3 but then increased again in weeks 6 and 12, while symptoms were continuing to decrease (Fig 3). The role of SP in allergic
rhinitis merits further investigation.
In the real acupuncture group, nasal itch, eye itch, sneezing,
runny nose, and unrefreshed sleep improved signicantly (Table 5).
Nasal itch, eye itch, and sneezing are all symptoms that are largely
mediated by the transient receptor potential vanilloid 1
(TRPV1).33e35 This nding suggests that acupuncture may modulate TRPV1 expression, sensitivity, and/or activation.36 Reductions
in rhinorrhea and unrefreshed sleep were probably not associated
with TRPV1 modulation.
There was a signicant negative correlation between PNIF and
MITO at week 12 (correlation coefcient 0.412; P .001) but
not at week 0 or week 9 (Table 6). However, when all recruited
participants at week 0 were included in the analysis (n 149) (as
opposed to only those who completed the study [n 110]), a signicant
negative
correlation
was
seen
(correlation
coefcient 0.220; P .004). Moderate to strong correlation
among different objective techniques to measure nasal airway
patency has been previously reported.37
There was a signicant positive correlation between Mini-RQLQ
nasal symptom domain scores and iTNSSs at week 0 (correlation
coefcient 0.484; P .001), at week 9 (correlation coefcient
0.541; P .001), and at week 12 (correlation coefcient 0.484;
P .001) (Table 6). A moderate correlation has been reported
among different subjective techniques of measuring nasal
obstruction.37 One notable difference between the outcomes produced by the iTNSS and the Mini-RQLQ nasal symptom domain
score can be seen in the time point comparisons. The iTNSS
revealed signicant improvements in nasal symptoms from baseline at week 9 and week 12 only in the real acupuncture group and
not in the sham group. However, the Mini-RQLQ revealed signicant improvements in nasal symptoms from baseline at week 9 and
week 12 in both the real acupuncture and sham acupuncture
groups (Table 3).
There was no correlation between objective measures of nasal
patency and subjective measures of perceived nasal obstruction at any
time point (Table 6). Lack of correlation between objective and subjective measures of nasal obstruction has been previously
reported.37e40 A complex interaction among psychological, neurologic, and mucosal factors appears to be involved in subjective sensations of nasal obstruction.38 In studies of allergic rhinitis, it is
valuable to include both objective and subjective measures of nasal
obstruction because they appear to provide different information.37e40
Although statistically signicant improvements in symptoms
and quality of life and reduced use of relief medication were

Abbreviations: iTNSS, instantaneous total nasal symptom score; MITO, mean inferior turbinate obstruction; MRQLQ stuffy e Mini-Rhinoconjunctivitis Quality of Life Questionnaire stuffy nose/blocked nose score; PNIF, peak nasal
inspiratory ow.

0.439 (P .001)
0.030 (P .79)
0.090 (P .36)
MRQLQ
stuffy

0.133 (P .22)
iTNSS

0.412 (P .001)
PNIF

Week 0
MITO
0.137 (P .17) 0.007 (P .94) 0.001 (P .99)
PNIF
0.137 (P .17)
0.046 (P .52) 0.006 (P .95)
iTNSS
0.007 (P .94) 0.046 (P .52)
0.512 (P .001)
MRQLQ 0.001 (P .99) 0.006 (P .95) 0.512 (P .001)
stuffy
Week 9
MITO
0.114 (P .28) 0.074 (P .45)
0.009 (P .93)
PNIF
0.114 (P .28)
0.026 (P .80) 0.004 (P .97)
iTNSS
0.074 (P .45) 0.026 (P .80)
0.565 (P .001)
MRQLQ
0.009 (P .93) 0.004 (P .97) 0.565 (P .001)
stuffy
Week 12
MITO

0.127 (P .20)

0.133 (P .22)

0.127 (P .20)
0.412 (P .001)

iTNSS
PNIF
MITO

Week 12

MRQLQ
stuffy
iTNSS
PNIF
Week 9

MITO
MRQLQ
stuffy
iTNSS
PNIF
MITO

Week 0

Table 6
Correlation Coefcients for Objective and Subjective Measurements of Nasal Obstruction

0.090
(P .36)
0.030
(P .79)
0.439
(P .001)

J.L. McDonald et al. / Ann Allergy Asthma Immunol xxx (2016) 1e9

MRQLQ
stuffy

observed after acupuncture, no statistically signicant reductions

in nasal airway clearance were seen. Because a previous study
found that acupuncture-induced improvements in nasal airways
begin to deteriorate 15 minutes after treatment, it is possible that
changes in nasal patency may not have been captured at 1-week
and 4-week follow-up.41
Signicant positive correlations between daily symptom diary
and daily medication diary mean weekly scores were seen only at
week 10 (correlation coefcient 0.396; P .023) in the sham
acupuncture group and at week 5 (correlation coefcient 0.440;
P .02) and week 6 (correlation coefcient 0.393; P .03) in the
real acupuncture group. This nding suggests that medication use,
as a behavior, was inuenced by factors other than the perceived
severity of symptoms. Reduction in the use of relief medications
has previously been used in allergic rhinitis studies as a measure of
clinical improvement; however, it may not be a reliable outcome
measure unless it is placed in context with other subjective and
objective measures of clinical status.9,42
Limitations
Potential bias may have occurred in the study because of sex,
age, disease, randomization bias, and negative bias due to a sham
protocol that was not inert. The convenience sample for the
study was 73.6% female; however, in 2012, it was estimated that
51.8% of Australian patients with allergic rhinitis were female.43
The age group from 18 to 45 years old in the study represents
less than 63.2% of the total population of Australians with allergic
rhinitis.43 The study excluded adults with asthma, but it is estimated that 40% of those with allergic rhinitis also have asthma
and as many as 80% to 95% of those with allergic asthma have
concomitant rhinitis.44 Nine individuals who completed the
study in the no acupuncture group reenrolled and were randomized to either the real or sham acupuncture groups but not to
the no acupuncture group again. Of these 9 individuals, 7
completed the study, which represented 6.4% of the total participants in the study, so any bias from randomization would
probably be small.
It is also likely that the use of a penetrating needle sham protocol may have introduced a negative bias into the study outcomes.
The sham acupuncture protocol used in this study was found to be
credible to participants but not inert. The use of sham acupuncture
protocols that are not inert can lead to underestimation of the effect
size of real acupuncture.31
Placebo and/or nocebo responses cannot adequately account for
the effects of sham acupuncture in this study because the exit
debrief questionnaire indicated that expectation and belief were
almost identically distributed between the real and sham
acupuncture groups (Table 7). Because differences between time
points within the real acupuncture group were statistically significant, but there were no signicant differences between groups for
total IgE or dust mite specic IgE, it is possible that the study was
underpowered to detect signicant differences in these
biomarkers.

Table 7
Exit Debrief Questionnaire: Results for the Real and Sham Acupuncture Groups
Group

No.

Thought
real group,
No. (%)

Thought
sham group,
No. (%)

Undecided,
No. (%)

Real acupuncture
Sham acupuncture

37a
35

17 (45.9)
17 (48.6)

18 (48.6)
16 (45.7)

2 (5.4)
2 (5.7)

a
An error occurred in the labeling of one of the envelopes. There were only 36
participants in the real acupuncture group and 37 in the sham acupuncture treatment. One sham acupuncture participant has been mislabeled as belonging to the
real acupuncture group. This error would have had little effect on the outcomes.

J.L. McDonald et al. / Ann Allergy Asthma Immunol xxx (2016) 1e9

The decision to use salivary analyses in this study was based on

previous work that suggested that saliva might provide a proxy for
upper airways with less discomfort and easier access than sampling
nasal uids.5 In future studies it is recommended that other technologies, such as ELIspot, T-cell cones, or Nanostring analysis, may provide a more accurate measure of cellular or tissue-level modulation.
Conclusions
Acupuncture treatment for persistent allergic rhinitis appeared
to have a signicant effect in decreasing the total IgE and allergen
specic IgE for house dust mite, which persisted at 4-week followup. A signicant down-regulation was also seen in SP, but the
course of this decrease did not correlate with the course of improvements in symptoms and quality of life. Symptoms and quality
of life improved signicantly and were still continuing to improve 4
weeks after treatment ceased. Evidence of immunomodulation
after acupuncture in allergic rhinitis may also have relevance to
other allergic conditions, such as allergic asthma.
Acknowledgments
The authors acknowledge the contribution of the Microbiology and
Immunology Research Group, Grifth University, for assistance
with laboratory assays and advice on statistical analysis.
Acupuncture needles for the study were donated by Helio Supply
Company Pty Ltd, Sydney, Australia.
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