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4331
Abstract. – OBJECTIVE: The present study
aimed to investigate the effects of a 4-week re -
peated oral intake of a quercetin-containing sup-
plement on allergen-induced reactions and rel-
ative subjective symptoms in Japanese adults
who complained of discomfort in the eyes and
nose.
SUBJEC TS AND METHODS: A randomized,
placebo-controlled, double-blind parallel-group
study was conducted on 66 subjects (22-78
years old) with allergic symptoms of pollino-
sis. The subjects were given the test product
(200 mg quercetin) or the control product (ve-
hicle) daily for 4 weeks. The Japanese Rhi-
no-conjunctivitis Quality of Life Questionnaire
(JRQLQ) scores and other tests were exam-
ined in each subject before and after starting
the product intake. A new food-grade bioavail-
able formulation of quercetin, Quercetin phyto-
some®, was used.
RE S ULT S : At 1:4 weeks after the start of the
supplement intake, several scores of JRQLQ,
including allergic symptoms, such as eye itch-
ing, sneezing, nasal discharge, and sleep dis-
order, were signicantly improved in the quer-
cetin-containing supplement group compared
with the placebo group. Furthermore, the quali-
ty of life of these subjects signicantly improved
based on the original questionnaire and visu-
al analog scale. Minor notable adverse effects
were noted throughout the study.
CONCLUSIONS: The results indicated that
oral intake of quercetin-containing supplements
might effectively reduce some allergy symp-
toms derived from pollinosis.
Key Words:
Quercetin, Healthy subject, Allergy symptoms, Na-
sal discharge, Sleep disorder.
Introduction
The prevalence of allergic diseases, such as
asthma, rhinitis, eczema, and food allergy, has
been rising in developed and developing coun-
tries1. This upward trend is particularly marked
in the prevalence of seasonal allergy (pollinosis)
in Japan, which is now called “a national disease”
aficting many people. According to the survey
conducted in 2016 by the Tokyo Metropolitan
Government2, the prevalence of Japanese ce-
dar (Sugi) pollinosis in Tokyo was estimated at
48.8% of the population. It has been theorized
that changes in environmental factors (indoor/
outdoor-sensitizing materials, such as allergens,
air pollution, and various infections) are respon-
sible for the high prevalence of such illnesses3. It
has also been suggested that the recent change
in the diet in Japan, involving changes in the
type and quantity of nutrients ingested, has been
increasing and aggravating allergic symptoms4.
Using synthetic drugs or herb medicines to treat
such illnesses can occasionally induce various
adverse reactions. Phytochemicals, such as avo-
noids and polysaccharides, are contained in many
plant-derived foods and have been reported to
have immunomodulating and anti-inammatory
actions5.
Quercetin is a kind of avonoid distribut-
ed widely in the vegetable kingdom. It is con-
tained in the Family Brassicaceae, plant-derived
foods (onion, Japanese tea, wine, fruits, etc.),
and herbs6. In Japan, quercetin is now used as an
existing food additive and a component of food
supplements. Numerous reports7 are available
concerning the physiological activity of querce-
European Review for Medical and Pharmacological Sciences 2022; 26: 4331-4345
S. YAMADA1, M. SHIRAI1, Y. INABA2, T. TAKARA3
1Center for Pharma-Food Research, Division of Pharmaceutical Sciences, Graduate School of
Integrative Pharmaceutical and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan
2Indena Japan Co. Ltd., Tokyo, Japan
3Medical Corporation Seishinkai, Takara Clinic, Tokyo, Japan
Corresponding Author: Shizuo Yamada, Ph.D; e-mail: yamada@u-shizuoka-ken.ac.jp
Effects of repeated oral intake of a
quercetin-containing supplement on allergic
reaction: a randomized, placebo-controlled,
double-blind parallel-group study
S. Yamada, M. Shirai, Y. Inaba, T. Takara
4332
tin, which ranges widely from anti-inammatory
action to hypotensive action, anti-allergic action,
a means of nutrition for athletes, and so forth.
Regarding the physiological activity of quercetin
against allergy, an in vitro study8 demonstrated
its effects in modulating the immune function
by inhibiting mast cell activity and histamine
release, suppressing eosinophilic inammation,
and other effects. This and some other in vitro
and in vivo studies8 suggested that quercetin is
effective against allergy. To date, however, the
efcacy of quercetin in humans has not been
evaluated sufciently. The lack of sufcient eval-
uation of its effectiveness in humans is probably
attributable to the low bioavailability of quercetin
in humans after oral ingestion.
Under such circumstances, the present study
was undertaken to evaluate the efcacy of quer-
cetin in healthy volunteers and mildly sick indi-
viduals with allergic symptoms, such as rhinitis
and ocular itching sensation, caused by antigens
(pollen or house dust). Quercetin with high sol-
ubility and trans-oral bioavailability by using
a new delivery system involving phytosome®
(Indena S.p.A, Milan, Italy) was used for this
study9,10 .
The present paper was originally published in
Japanese in the Japanese Pharmacology & Ther-
apeutics journal11.
Subject and Methods
This study was designed as a placebo-con-
trolled randomized, double-blind parallel-group
study. Before the start of the study, its protocol
was approved on 19 November 2019 by the
Medical Corporation Seishinkai, Takara Clinic
(Approval No. 1911-1911-IJ01-01-TC) and regis-
tered with UMIC-CTR (UMIN000038765) on
3 December 2019. It was carried out under suf-
cient consideration of individual participants’
human rights, safety, and well-being following
the Declaration of Helsinki, the Clinical Study
Act, and the Clinical Study Act Enforcement
Regulations.
Management of study participants was as-
signed to the clinical research organization
ORTHOMEDICO Inc. Study participants were
recruited by holding a preliminary orientation
meeting about the study. Individuals who intend-
ed to participate in the study were informed about
the study design. Written consent was obtained
from the study participants later at each study
site. The study lasted from 3 December 2019 to 4
April 2020, with no changes to the study protocol
during this period.
Subjects
Of the 90 Japanese adults complaining of
eye and/or nose discomfort and managed at the
Medical Corporation Seishinkai, Takara Clinic,
66 were enrolled in this study. A major inclusion
criterion was relative high nose/eye symptoms
scores with the Japanese Rhino-conjunctivitis
Quality of Life Questionnaire (JRQLQ) during
the screening and pre-medication evaluation.
Individuals satisfying all inclusion criteria and
falling under the exclusion criteria were eligible
for the study. The percentage of subjects with
JRQLQ nose/eye symptom scores in the normal
range was ≥50% of the total number of subjects
(subjects with normal range scores + subjects
with mildly abnormal scores). Written informed
consent was obtained from all subjects before
enrollment in the study.
Inclusion Criteria
Inclusion criteria were: (1) Individuals judged
by the Principal Investigator to be eligible for the
study without any problem and (2) individuals
whose JRQLQ nose/eye symptom score was rel-
atively high in the screening and pre-medication
evaluation. Denition of terms: “Subjects with
normal range of scores” indicate the individuals
having allergic reactions in the nose and/or eye
(including those having shown such responses
before) but taking no anti-allergy drug before and
during the study period. “Subjects with mildly
abnormal scores” indicate the individuals having
allergic reactions of the nose and/or eye (includ-
ing those having shown such responses before)
and occasionally (not routinely) taking the an-
ti-allergy drug(s) before and during the study
period. “Occasionally” means intake of medi-
cation as needed. “Routinely” means periodical
drug intake regardless of the presence/absence of
symptoms.
Exclusion Criteria
The exclusion criteria were the following:
1. Patients currently receiving or having a his-
tory of receiving treatment for malignant tu-
mors, heart failure, or myocardial infarction.
2. Patients using a pacemaker or an implanted
debrillator.
3. Patients currently receiving treatment for ar-
rhythmia, liver dysfunction, kidney dysfunc-
Effects of intake of a quercetin-containing supplement on allergic reaction
4333
tion, cerebrovascular disorders, rheumatoid
arthritis, diabetes mellitus, dyslipidemia, hy-
pertension, or other chronic illness.
4. Individuals routinely ingesting foods for
specied health uses, foods for function
claims, or other foods/ beverages for poten-
tial functional claims.
5. Patients requiring continuous use of drugs
possibly affecting the nose/eye allergic symp-
toms (anti-allergy drugs, antihistamines,
steroids, vasoconstrictors, antihypertensive
agents, etc.) during the study period.
6. Individuals routinely taking drugs (including
herb medicines) and/or supplements.
7. Individuals allergic to any medicine or test
food-related food.
8. Individuals unable to take the test food by
the method and at the dose level outlined in
the protocol.
9. Individuals planning to make an overseas
trip during the study period.
10. Individuals habitually practicing nose gur-
gling.
11. Pregnant or lactating women or women who
intended to become pregnant during the
study period.
12. Individuals having participated in any other
clinical study during the 3-month period
before acquiring consent to this study or
planning to participate in any further clinical
study during the study period.
13. Other individuals judged by the Principal In-
vestigator to be inappropriate for this study.
Randomization and Blinding
Of the 90 individuals satisfying all of the in-
clusion criteria, 24 were excluded as they fell into
any of the exclusion criteria, and the remaining
66 were enrolled in the study. For these 66 sub-
jects, the allocation sequence was determined
with Statlight #11 Ver.2.10 (Yukms Co., Ltd.,
Tokyo, Japan). Individual subjects were randomly
allocated, in a stratied ratio of 1:1, to the placebo
food group or the test food group. The allocation
table was sealed and stored until the completion
of the study. It was unsealed after the completion
of the study.
Test Food
The test food was given for 4 weeks, from 24
February to 4 April 2020. The test food contains
quercetin as a major active ingredient. The solu-
bility and trans-oral bioavailability of quercetin
in the test food was improved by a new delivery
system involving lecithin9,10 . This test food and
the placebo food were supplied from Indena
S.p.A (Milan, Italy). The safety of the test food
had been conrmed in previous studies9,10 with
triathlon athletes, i.e., a study involving 2-week
ingestion of the test food 500 mg/day (containing
200 mg quercetin) and another study involving a
single dose of the test food 250-500 mg/day. The
subjects of the present study ingested the test
food or the placebo food (containing 50 mg quer-
cetin or the same quantity of vehicle per tablet)
at a daily dose level of four tablets divided into
two doses (breakfast and supper; two tablets each
time) together with water. It was conrmed in
advance that distinction between test and placebo
foods through taste and external appearance was
not possible.
Evaluation Method
Test and evaluation were conducted before
starting the study and 2 and 4 weeks after starting
food ingestion. Subjects who withdrew their con-
sent to the study or ceased ingesting the test or
placebo food were discontinued from the study.
Each complication or adverse event reported by
subjects was recorded. Each subject was instruct-
ed to keep their lifestyle unchanged during the
test/placebo food ingestion period.
Tests
The general test included height, body weight,
BMI, body-fat ratio, blood pressure, and heart
rate. Blood tests included measurement of white
blood cells, red blood cells, hemoglobin, hemato-
crit, mean corpuscular volume, mean corpuscular
hemoglobin, mean corpuscular hemoglobin con-
centration, platelet count, differential leukocyte
count (percentage and count of neutrophils, lym-
phocytes, monocytes, eosinophils, and basophils),
aspartate aminotransferase, alanine transami-
nase, γ-glutamyl transferase, alkaline phospha-
tase, lactate dehydrogenase, leukocyte alkaline
phosphatase, total bilirubin, direct bilirubin, in-
direct bilirubin, cholinesterase, total protein, urea
nitrogen, creatinine, uric acid, creatine kinase
(CK), calcium, serum amylase, total cholesterol,
HDL-cholesterol, LDL-cholesterol, triglyceride,
glycoalbumin, serum iron (Fe), sodium (Na),
potassium (K), chlorine (Cl), inorganic phos-
phorus, glucose, and hemoglobin A1c (HbA1c).
Urinalysis covered protein (qualitative), glucose
(qualitative), urobilinogen (qualitative), bilirubin
(qualitative), occult blood reaction (qualitative),
ketone body (qualitative), specic gravity, and
S. Yamada, M. Shirai, Y. Inaba, T. Takara
4334
pH. Virological and immunoserological tests
covered hemoglobin antigen, hepatitis C virus
antibody III, HIV antigen/antibody, and syphilis
(qualitative). Physical examinations, blood tests,
urinalysis, and allergic rhinitis-related tests were
conducted at baseline and 2 and 4 weeks af-
ter test/placebo food ingestion. Safety evaluation
items comprised adverse events and adverse reac-
tions, which were evaluated based on the physical
test, blood test, and urinalysis.
Primary Endpoints
Primary Endpoints were evaluated using the
JRQLQ12-15 .
Secondary Endpoints
Secondary endpoints were evaluated using the
severity grading of allergic rhinitis symptoms,
nasal discharge test (nasal discharge eosinophil
count), blood test (unspecic IgE, specic IgE
[Dermatophagoides pteronyssinus, Japanese ce-
dar, Hinoki cypress, house dust]), and a home-
made questionnaire.
Statistical Analysis
For comparison between the placebo group
and the test food group, the difference in the
score of each test parameter between the score
at the baseline and the score at 2 weeks after
the start of test/placebo food ingestion and upon
completion of test/placebo food ingestion was
subjected to repeated measures ANOVA. The
baseline served as the covariable and the time
point, group, and time-group interactions served
as factors. An adjustment was not made for mul-
tiple tests involving multiple items and multiple
time points. Mann-Whitney U-test was employed
for inter-group comparison of responses to ques-
tions or the classied values. For inter-group
comparison at the baseline, the chi-square test (on
gender and age) and unpaired t-test (on cognitive
function test) were employed. Statistical analysis
was performed using the software SPSS Statis-
tics, ver.23.0 (IBM Corp., Armonk, NY, USA),
and the signicance level was set at p<0.05%
(two-tailed) in each test.
In the safety analysis, an inter-group compar-
ison was conducted on the data from physical
measurement (excluding height), physical exam-
ination, and peripheral blood test at 2 and 4
weeks after starting test/placebo food ingestion
using ANCOVA in which the baseline served as
the covariable, and the group served as a factor.
Results
Subjects Analyzed
A ow diagram of subjects is given in Figure
1. The study was carried out as scheduled, with-
out any protocol change. Of the 90 individuals
having consented to participate in the study, 66
satisfying all the inclusion criteria and falling un-
der none of the exclusion criteria were enrolled in
the study. Afterward, three subjects were found
to fall under any of the exclusion criteria, and
another three quit the study after the start of the
intervention. Thus, 60 subjects were eventually
included in the per-protocol set and the analysis.
The safety analysis set consisted of 64 subjects,
and the per-protocol set consisted of 60 subjects.
In terms of sex, the test food group consisted of
18 women and 12 men, and the placebo group
consisted of 15 women and 15 men. In terms of
age, the test food group consisted of three sub-
jects at age 20-29 years, three at age 30-39 years,
12 at 40-49 years, six at 50 years 59 years, ve at
60-69 years and one at 70-79 years. The placebo
group consisted of three subjects at age 20-29
years, ve at 30-39 years, 10 at 40-49 years, sev-
en at 50-59 years, two at 60-69 years, and two at
70-79 years. Background variables and blood test
results of subjects are given in Table I. There was
no signicant difference between the two groups.
Efficacy Evaluation
Primary endpoints
Table II shows the absolute value of each
JRQLQ score in both groups. Table II gives the
Figur e 1. Flow diagram of the enrolled subjects.
Effects of intake of a quercetin-containing supplement on allergic reaction
4335
magnitude of change in each score at 2 weeks
(2W) and 4 weeks (4W) after starting ingestion
from the pre-start baseline. The absolute values
of JRQLQ total score, Quality Of Life (QOL)
total score, sleep score, and physical score were
signicantly lower in the test food group than in
the placebo group (Table II). The magnitude of
change in sleep and physical score at 4W was
signicant between the two groups (Table II).
The decrease in the score of each item of
JRQLQ indicates a tendency for improvement.
The absolute value of sleep score (mean ± SD) in
the test food group was 1.7 ± 1.2 before starting
ingestion, 1.1 ± 0.9 at 2W, and 0.8 ± 0.8 at 4W.
The corresponding value in the placebo group
was 1.5 ± 1.1 before starting ingestion, 1.2 ± 0.8
at 2W, and 1.4 ± 0.9 at 4W. Thus, the magnitude
of change in sleep score was signicantly smaller
in the test food group (4W; -1.0 ± 0.9) than in the
placebo group (4W; -0.1 ± 1.0; p=0.00), as shown
in Table II. The absolute value of the physical
score in the test food group was 3.6 ± 2.5 before
starting ingestion, 2.3 ± 1.6 at 2W, and 1.5 ± 1.7
at 4W. The corresponding value in the placebo
group was 3.8 ± 2.1 before starting ingestion, 2.9
± 1.6 at 2W, and 2.8 ± 1.6 at 4W.
Thus, as shown in Table II, the magnitude of
change in physical scores was signicantly small-
er in the test food group (4W; -2.1 ± 1.8) than in
the placebo group (4W; -1.0 ± 2.0; p=0.03).
Of the JRQLQ items showing signicant in-
ter-group differences, the following had signi-
cantly lower scores in the test food group than
in the placebo group, as shown in Table III:
“sneezing” ( p=0.04), “decrease in thinking pow-
er” (difculty in focusing; p=0.01), “disturbance
in outdoor activities, such as sports and picnics”
(p=0.01), “sleep disorder” (p=0.01), “malaise”
(p=0.00), “tendency to fatigue” (p=0.02), and
“face scale” (p=0.03).
Secondary endpoints
Of the items showing signicant inter-group
differences in severity grading of allergic rhinitis,
the following had signicantly lower scores in
the test food group than in the placebo group, as
shown in Table IV: “sneezing” (p=0.01), “rhinor-
rhea” (p=0.01), and “disturbance in daily living”
(p=0.01). The “ocular itching sensation” score
was signicantly low at 1 week after the start of
ingestion ( p= 0.02).
In the nasal discharge test, the nasal discharge
eosinophil count at 2W was signicantly lower
in the test food group than in the placebo group.
Still, there was no signicant difference in this
parameter between the two groups when exam-
ined at 4W (Table V). Blood test (unspecic IgE,
specic IgE [Dermatophagoides pteronyssinus,
Japanese cedar, Hinoki cypress, and house dust])
Table I. Background variables and blood test results of subjects.
Variable Active group (n = 32) Placebo group (n = 32) p-value
Sex (male/female) 13/19 17/15 0.45
Age (years) 46.8 (13.0) 46.9 (13.0) 0.92
Height (cm) 165.4 (8.0) 165.2 (8.6) 0.92
Weight (kg) 61.3 (13.0) 65.0 (13.9) 0.27
BMI (kg/m2) 22.3 (3.5) 23.7 (3.7) 0.13
Body-fat percentage (%) 23.4 (6.4) 24.7 (6.0) 0.41
Blood pressure (mmHg):
• Systolic 118.5 (14.3) 115.0 (12.4) 0.30
• Diastolic 75.7 (10.6) 74.7 (10.8) 0.71
Pulse 74.0 (9.0) 74.7 (8.4) 0.75
Blood biochemistry:
• AST (GOT) (U/L) 21.3 (9.2) 22.3 (5.8) 0.60
• ALT (GPT) (U/L) 19.2 (13.0) 20.4 (10.8) 0.69
• γ-GTP (IU/L) 25.6 (16.9) 26.6 (21.2) 0.84
• Total cholesterol (mg/dL) 208.8 (27.3) 211.8 (35.7) 0.71
• Triglyceride (mg/dL) 78.8 (35.8) 95.4 (56.3) 0.17
• Glucose (mg/dL) 86.6 (9.5) 83.8 (7.8) 0.21
• HbA1c (NGSP) (%) 5.3 (0.2) 5.4 (0.3) 0.64
• HDL cholesterol (mg/dL) 71.9 (17.4) 62.3 (15.5) 0.02
• LDL cholesterol (mg/dL) 118.4 (29.7) 129.4 (31.6) 0.16
Values in bold are signicant (p<0.05). Continuous variables are shown as mean (SD). SD, standard deviation.
S. Yamada, M. Shirai, Y. Inaba, T. Takara
4336
revealed no signicant difference in any param-
eter between the test food group and the placebo
group.
According to the original QOL questionnaire
results using the visual analogue scale (VAS)
method, there was no signicant inter-group dif-
ference in any item, as shown in Table VI (ab-
solute values). However, the scores of “itching
sensation other than ocular/nasal itching sensa-
tion” (p=0.04) and “rash (skin below the nose,
etc.)” (p=0.01) were signicantly lower in the
test food group than in the placebo group as a
result of interactions. In addition, in terms of the
magnitude of change (Table VI), no item showed
a signicant inter-group difference reecting im-
provement in the test food group. Yet, the score
of “rash, (the skin below the nose, etc.)” (p=0.02)
was signicantly lower in the test food group than
in the placebo group as a result of interactions.
Safety Evaluation
Of the items showing signicant inter-group
differences in physical measurement and physi-
cal examination, the following had signicantly
lower scores in the test food group than in the pla-
cebo group: “systolic blood pressure” ( p= 0.003)
and “diastolic blood pressure” (p=0.015). No item
of urinalysis showed a signicant difference be-
tween the test food group and the placebo group.
The blood test showed only blood glucose level
to be signicantly lower in the test food group
than in the placebo group (p=0.021). All the
Table II. Inuence on Japanese R hino-conjunctivitis Quality of Life Questionnaire expressed for both absolute values and
magnitude of change.
Absolute value Magnitude of change
Active group Placebo group Active group Placebo group
Variable (n = 30) (n = 30) p-value (n = 30) (n = 30) p-value
JRQLQ
2W 25.8 (14.6) 29.7 (13.1) 0.23 -8.9 (15.5) -5.0 (16.9) 0.36
Total score
4W 19.1 (12.1) 26.3 (15.0) 0.04 -15.6 (17.5) -8.4 (18.5) 0.13
Nose/eye symptoms
2W 8.9 (4.7) 9.8 (4.7) 0.47 -1.2 (4.9) -0.5 (4.7) 0.59
4W 7.4 (4.1) 8.7 (4.8) 0.28 -2.6 (5.1) -1.6 (5.3) 0.44
Nose score
2W 5.9 (3.6) 6.8 (3.6) 0.27 -1.1 (3.2) -0.2 (3.6) 0.34
4W 4.8 (2.4) 6.0 (3.4) 0.13 -2.1 (3.4) -1.1 (3.5) 0.27
Eye score
2W 3.0 (1.8) 3.0 (1.7) 0.85 -0.1 (2.0) -0.3 (1.8) 0.74
4W 2.6 (2.0) 2.8 (1.9) 0.78 -0.5 (2.3) -0.5 (2.2) 0.95
QOL total score
2W 16.9 (11.1) 19.9 (9.8) 0.21 -7.7 (11.6) -4.5 (13.9) 0.34
4W 11.6 (9.1) 17.6 (11.4) 0.02 -12.9 (13.8) - 6.8 (14.1) 0.10
Activities of daily living score
2W 5.5 (4.0) 5.9 (2.8) 0.61 -1.9 (4.7) -1.5 (3.8) 0.72
4W 3.9 (3.0) 5.4 (3.3) 0.06 -3.5 (4.8) -2.1 (4.2) 0.21
Outdoor activity score
2W 2.0 (2.1) 2.2 (1.3) 0.73 -0.4 (1.8) -0.3 (2.2) 0.90
4W 1.1 (1.4) 1.8 (1.3) 0.09 -1.2 (1.9) -0.7 (2.2) 0.34
Social activity score
2W 2.1 (2.1) 2.9 (1.8) 0.13 -0.9 (2.3) -0.2 (2.8) 0.31
4W 1.5 (1.7) 2.1 (1.9) 0.20 -1.5 (3.0) -1.0 (2.5) 0.46
Sleep score
2W 1.1 (0.9) 1.2 (0.8) 0.34 - 0.6 (0.9) -0.3 (0.9) 0.24
4W 0.8 (0.8) 1.4 (0.9) 0.00 -1.0 (0.9) -0.1 (1.0) 0.00
Physical score
2W 2.3 (1.6) 2.9 (1.6) 0.12 -1.3 (1.9) -0.9 (2.0) 0.43
4W 1.5 (1.7) 2.8 (1.6) 0.00 -2.1 (1.8) -1.0 (2.0) 0.03
Mental life score
2W 3.8 (3.4) 4.7 (3.6) 0.13 -2.6 (3.0) -1.3 (4.0) 0.14
4W 2.8 (2.8) 4.1 (3.7) 0.08 -3.6 (3.7) -1.9 (4.3) 0.11
Effects of intake of a quercetin-containing supplement on allergic reaction
4337
Continued
Table III. Inuence on Japanese Rhino-conjunctivitis Quality of Life Questionnaire items.
Active group Placebo group
(n = 30) (n = 30)
Variable
(Question item score) Median Q1 Q3 Median Q1 Q3 p-value
Runny nose B 2.0 1.0 2.0 1.5 1.0 2.0 0.64
2W 1.0 1.0 2.0 2.0 1.0 2.0 0.20
4W 1.0 1.0 1.0 1.0 1.0 2.0 0.23
Sneezing B 1.5 1.0 2.0 2.0 1.0 2.8 0.65
2W 1.0 1.0 2.0 1.5 1.0 2.8 0.39
4W 1.0 1.0 2.0 1.5 1.0 2.0 0.04
Nasal congestion B 2.0 1.0 2.0 2.0 1.0 3.0 0.95
2W 1.0 1.0 2.0 1.0 1.0 2.8 0.38
4W 1.0 1.0 1.0 1.0 1.0 2.0 0.51
Nasal itching sensation B 1.0 1.0 2.0 2.0 1.0 2.8 0.46
2W 1.0 1.0 2.0 1.5 1.0 2.0 0.37
4W 1.0 1.0 2.0 1.0 1.0 2.0 0.87
Ocular itching sensation B 2.0 1.0 2.0 2.0 1.0 3.0 0.52
2W 2.0 1.0 3.0 2.0 1.0 3.0 0.84
4W 1.5 1.0 2.0 2.0 1.0 2.0 0.55
Teary eyes B 1.0 1.0 2.0 1.0 1.0 2.0 0.79
2W 1.0 0.3 1.8 1.0 0.3 1.0 0.80
4W 1.0 0.0 1.8 1.0 0.0 1.0 0.98
Disturbed learning/job/housework B 1.0 1.0 2.0 1.0 1.0 2.0 0.84
2W 1.0 0.0 2.0 1.0 1.0 1.8 0.63
4W 1.0 0.0 1.0 1.0 1.0 1.8 0.21
Difculty in mental focusing B 2.0 1.0 2.0 2.0 1.0 2.0 0.83
2W 1.0 1.0 2.0 1.0 1.0 2.0 0.36
4W 1.0 0.0 1.0 1.0 1.0 2.0 0.12
Decrease in thin king power B 1.0 1.0 2.8 1.0 1.0 2.0 0.81
(difculty in focusing) 2W 1.0 0.0 1.0 1.0 1.0 2.0 0.13
4W 1.0 0.0 1.0 1.0 1.0 1.0 0.01
Inconvenience in reading B 1.0 1.0 2.8 1.0 1.0 2.0 0.45
newspapers/books 2W 1.0 1.0 2.0 1.0 1.0 2.0 0.96
4W 1.0 0.0 1.0 1.0 0.0 1.0 0.46
Reduced memor y B 1.0 0.3 2.0 1.0 1.0 2.0 0.88
2W 1.0 0.0 1.0 1.0 1.0 1.0 0.82
4W 1.0 0.0 1.0 1.0 0.3 1.0 0.27
Disturbance in outdoor activities B 1.0 0.3 2.0 1.0 0.3 2.0 0.74
(sports, picnics, etc.) 2W 1.0 0.0 1.8 1.0 1.0 2.0 0.34
4W 0.0 0.0 1.0 1.0 0.0 1.8 0.01
Disturbance in going out B 1.0 0.0 2.0 1.0 1.0 2.0 0.61
(tendency to avoid going out) 2W 1.0 0.0 1.8 1.0 1.0 1.8 0.32
4W 0.5 0.0 1.0 1.0 0.0 1.0 0.38
Disturbance in social activity B 1.0 0.0 2.0 1.0 0.0 1.0 0.82
(tendency to avoid it) 2W 0.5 0.0 1.0 1.0 1.0 1.0 0.17
4W 0.0 0.0 1.0 1.0 0.0 1.0 0.10
Disturbance in conversation/ B 1.0 0.0 2.0 1.0 1.0 1.8 0.63
telephone call with/to other people 2W 1.0 0.0 1.0 1.0 0.3 1.0 0.28
4W 0.0 0.0 1.0 1.0 0.0 1.0 0.53
Nervous with surrounding people B 1.0 0.0 2.0 1.0 0.0 2.0 0.49
2W 1.0 0.0 1.0 1.0 0.3 1.0 0.08
4W 0.0 0.0 1.0 0.5 0.0 1.0 0.34
S. Yamada, M. Shirai, Y. Inaba, T. Takara
4338
signicant inter-group differences observed in
parameters were variations within the criterion
range of the parameters concerned. No adverse
event attributable to ingestion of the test food was
observed during the study period.
Discussion
Allergy-like symptoms of type I allergy are
caused by excessive mucus secretion and mast
cell degranulation due to excessive IgE formation
upon allergen invasion into the living body16.
Type 1 allergy is involved in allergic rhinitis,
which presents with nasal symptoms (sneezing,
nasal discharge, nasal congestion, etc.) and oth-
er symptoms, such as headache and difculty
concentrating, resulting in reduced QOL13. In
the eyes, conjunctivitis can develop, resulting in
congestion, ocular itching sensation, lacrimation,
and so on14,17. Allergic rhinitis also involves in-
creasing nasal discharge eosinophil count arising
from exposure to allergens. This change is used
as one of the signs of diagnosing allergic rhini-
tis18. Suppression of degranulation16 and inhibi-
tion of the binding of histamine (released as a re-
sult of degranulation) to the receptor19 are known
as valid approaches to alleviation or suppression
of these symptoms of allergic reactions.
Regarding the physiological activity of querce-
tin contained in the test food for this study, numer-
ous scholars8 using cells and animals demonstrated
its effects in inhibiting mast cell activity and his-
tamine release, suppressing inammation induced
by eosinophil increase or activation, adjusting the
immune function, etc. Additionally, quercetin in-
hibits the formation and release of histamine and
other allergic/proinammatory substances by sta-
bilizing the mast cell membrane19. It has also been
reported20 that quercetin inhibits the activation
Values in bold are signicant (p<0.05). JRQLQ, Japanese Rhino-conjunctivitis Quality of Life Questionnaire. B, before start of
ingestion. 2W, 2 weeks after start of ingestion. 4W, 4 weeks after start of ingestion.
Table III (Continued). Inuence on Japanese Rhino-conjunctivitis Quality of Life Questionnaire items.
Active group Placebo group
(n = 30) (n = 30)
Variable
(Question item score) Median Q1 Q3 Median Q1 Q3 p-value
Sleep disorder B 2.0 1.0 3.0 1.5 1.0 2.0 0.44
2W 1.0 0.3 2.0 1.0 1.0 2.0 0.66
4W 1.0 0.0 1.0 1.0 1.0 2.0 0.01
Malaise B 1.5 1.0 3.0 2.0 1.0 3.0 0.54
2W 1.0 1.0 1.0 1.0 1.0 2.0 0.08
4W 0.0 0.0 1.0 1.0 1.0 2.0 0.00
Tendency to fatigue B 2.0 1.0 3.0 2.0 1.0 3.0 0.85
2W 1.0 1.0 2.0 2.0 1.0 2.0 0.13
4W 1.0 0.0 1.0 1.0 1.0 2.0 0.02
Feeling gloomy B 2.0 1.0 3.0 2.0 1.0 2.8 0.94
2W 1.0 0.0 1.8 1.0 0.3 2.0 0.26
4W 1.0 0.0 1.0 1.0 1.0 2.0 0.09
Irritation B 1.5 1.0 2.0 1.0 1.0 2.0 0.63
2W 1.0 0.0 1.0 1.0 0.0 2.0 0.31
4W 1.0 0.0 1.0 1.0 0.0 1.8 0.30
Depressed mood B 2.0 1.0 2.0 1.0 1.0 2.0 0.40
2W 1.0 0.0 1.0 1.0 0.0 2.0 0.61
4W 1.0 0.0 1.0 1.0 0.0 1.0 0.66
Discontent with daily life B 1.0 1.0 2.0 1.0 1.0 2.0 0.95
2W 1.0 0.0 1.8 1.0 1.0 2.0 0.25
4W 1.0 0.0 1.0 1.0 0.0 1.0 0.19
Face scale B 2.0 1.3 3.0 2.0 2.0 3.0 0.90
2W 2.0 1.0 2.0 2.0 2.0 3.0 0.23
4W 1.0 1.0 2.0 2.0 1.0 3.0 0.03
Effects of intake of a quercetin-containing supplement on allergic reaction
4339
of human mast cells by suppressing the inow of
calcium ions, releasing inammatory cytokines,
and activating protein kinase, which is involved
in allergic reactions. In a study21 using mast cells
derived from the nasal mucosa of Japanese pa-
tients with perennial allergic rhinitis, the addition
of quercetin reduced the amount of histamine
release signicantly. Therefore, ingestion of quer-
cetin-containing food is expected to manifest an
anti-allergic activity through suppression of mast
cell activity, inhibition of histamine release, and
suppression of eosinophil increase.
Allergic rhinitis can be divided into two types
(seasonal and perennial). Seasonal allergic rhini-
tis often assumes the form of pollinosis with pol-
len serving as an allergy, while perennial allergic
rhinitis is primarily caused by allergens, such
as house dust and house mites14. In Tokyo, Japa-
nese cedar (Sugi) pollen prevails in mid-February
through late March, and Hinoki cypress pollen
increases in late March to mid-April22. Therefore,
we can predict that the pollen spread level gets
higher in late February to early April than in
other seasons, and symptoms of seasonal allergic
rhinitis are more likely to be induced during this
period. For this reason, the present study was
designed to evaluate the inuence of 4-week
continuous ingestion of quercetin-containing test
Values in bold are signicant (p<0.05). B, before start of ingestion (1 week). 1W, 1 week after start of ingestion. 2W, 2 weeks
after start of ingestion. 3W, 3 weeks after start of ingestion. 4W, 4 weeks after start of ingestion. SD, standard deviation.
Table IV. Inuence on severity grading of allergic rhinitis.
Active group Placebo group
(n = 30) (n = 30)
Variable
(score) Median Q1 Q3 Median Q1 Q3 p-value
Sneezing B 1.0 1.0 2.0 2.0 1.0 2.0 0.04
1W 1.0 1.0 2.0 1.0 1.0 2.0 0.19
2W 1.0 1.0 2.0 1.0 1.0 2.0 0.44
3W 1.0 1.0 1.0 1.0 1.0 2.0 0.04
4W 1.0 1.0 1.0 1.0 1.0 2.0 0.01
Rhinorrhea B 1.0 1.0 2.0 2.0 1.0 3.0 0.04
1W 1.0 1.0 2.0 2.0 1.0 3.0 0.01
2W 1.0 1.0 2.0 2.0 1.0 2.0 0.05
3W 1.0 1.0 1.0 1.5 1.0 2.0 0.01
4W 1.0 1.0 1.0 1.5 1.0 2.0 0.01
Nasal congestion B 1.0 0.0 1.0 1.0 0.0 2.0 0.40
1W 1.0 0.0 1.0 1.0 0.0 2.0 0.19
2W 1.0 0.0 1.0 1.0 0.0 1.8 0.45
3W 0.0 0.0 1.0 1.0 0.0 1.8 0.12
4W 0.0 0.0 1.0 1.0 0.0 1.8 0.22
Ocular itching sensation B 1.0 1.0 2.0 2.0 1.0 2.0 0.09
1W 1.0 1.0 2.0 2.0 1.0 2.0 0.02
2W 1.0 0.3 2.0 1.0 1.0 2.0 0.20
3W 1.0 0.3 2.0 1.5 1.0 2.0 0.08
4W 1.0 0.0 2.0 1.0 1.0 2.0 0.22
Lacr imation B 1.0 0.0 1.0 1.0 0.0 1.0 0.97
1W 1.0 0.0 1.0 0.5 0.0 1.0 0.82
2W 0.0 0.0 1.0 0.0 0.0 1.0 0.75
3W 0.0 0.0 1.0 1.0 0.0 1.0 0.38
4W 0.0 0.0 1.0 0.5 0.0 1.0 0.64
Disturbance in daily living B 1.0 0.0 1.0 1.0 0.3 2.0 0.42
1W 1.0 0.0 1.0 1.0 0.3 2.0 0.20
2W 0.5 0.0 1.0 1.0 1.0 1.8 0.03
3W 0.0 0.0 1.0 1.0 1.0 2.0 0.00
4W 0.0 0.0 1.0 1.0 1.0 1.0 0.01
S. Yamada, M. Shirai, Y. Inaba, T. Takara
4340
food on subjective symptoms related to allergic
reactions to allergens in Japanese adults of both
sexes having eye and/or nose discomfort during
the period from late February to early April (the
intervention period).
In the evaluation of each score of JRQLQ as
a primary effect of the test food, signicant im-
provement was noted in QOL total score (absolute
value), sleep score (absolute value and magnitude
of change), and physical score (absolute value
and magnitude of change) (Table II). In a post-
hoc analysis, the JRQLQ total score (absolute
value), QOL total score (absolute value), sleep
score (absolute value and magnitude of change),
and physical score (absolute value and magnitude
of change) at 4 weeks after the start of ingestion
were signicantly lower in the test food group
than in the placebo group (Table II) Since the
JRQLQ total score in this study is the total of
nose symptom score and QOL total score, it
seems likely that the signicant difference in
QOL total score was reected in the signicant
difference in JRQLQ total score. A lower JRQLQ
score indicates better QOL; ingestion of the test
food has improved the QOL23.
The JRQLQ is designed to calculate each of
the nose/eye symptom score, nose score, and eye
score as the average in each eld based on the
5-grade rating of six symptoms, i.e., runny nose,
sneezing, nasal congestion, nasal itching sensa-
tion, ocular itching sensation, and teary eyes23.
In addition, the 17 items related to QOL (5-grade
rating) are classied by eld, and the mean score
of each of them is evaluated. The daily living
score is calculated as the mean of the scores of
“disturbance in learning/job/housework,” “dif-
culty in mental focusing,” “decrease in thinking
power (difculty in focusing),” “inconvenience
in reading newspapers/books,” and “decrease in
memory”. The outdoor activity score is calculated
as the mean of the sores of “disturbance in sports,
picnics, etc.” and “disturbance in going out (ten-
dency to avoid going out).” The social activity
score is calculated as the mean of scores of “dis-
turbance in social activity (tendency to avoid it),”
“disturbance in conversation/telephone call with/
to other people,” and “nervous with surrounding
people.” The sleep score is the mean of the score
of “sleep disorder.” The mental quality of life
score is the mean of scores of “feeling gloomy,”
“irritation,” “depressed mood,” and “discontent
with daily living”23. The scores in these six elds
are added to yield a total QOL score. The face
scale, which indicates the comprehensive status
Values in bold are signicant (p<0.05). B, before start of ingestion. 2W, 2 weeks after start of ingestion. 4W, 4 weeks after start
of ingestion.
Table V. Inuence on nasal discharge neutrophil count and specic IgE in nasal discharge test and blood test.
Active group Placebo group
(n = 30) (n = 30)
Variable
(score) Median Q1 Q3 Median Q1 Q3 p-value
Nasal discharge eosinophil count B 0.0 0.0 1.0 0.0 0.0 1.0 0.70
2W 0.0 0.0 1.0 1.0 0.0 1.0 0.02
4W 0.0 0.0 1.0 1.0 0.0 2.0 0.09
Dermatophagoides pteronyssinus B 1.5 0.0 3.0 3.0 0.0 3.0 0.12
2W 1.5 0.0 3.0 3.0 0.0 3.0 0.12
4W 1.0 0.0 3.0 3.0 0.0 3.0 0.08
Japanese cedar B 3.0 1.0 3.8 3.0 2.0 3.8 0.83
2W 2.5 1.0 3.8 3.0 2.0 3.8 0.47
4W 3.0 1.0 3.8 3.0 2.0 4.0 0.47
Hinoki cypress B 1.0 0.0 2.8 1.5 0.0 2.0 0.94
2W 1.0 0.0 2.0 2.0 0.0 2.0 0.74
4W 1.0 0.0 2.0 2.0 0.0 2.0 0.57
House dust B 1.5 0.0 3.0 3.0 0.0 3.0 0.18
2W 1.5 0.0 3.0 2.5 0.0 3.0 0.19
4W 1.5 0.0 3.0 2.5 0.0 3.0 0.21
Effects of intake of a quercetin-containing supplement on allergic reaction
4341
of QOL, is used in combination with the score of
each eld related to nose/eye symptoms and QOL
for evaluation of QOL related to allergic rhinitis.
In the present study, the scores of “sneezing,”
“decrease in thinking power (difculty in focus-
ing),” “disturbance in outdoor activities such as
sports and picnics,” “sleep disorder,” “malaise,”
“tendency to fatigue,” and “face scale” at 4W
were signicantly lower in the test food group
than in the placebo group (Table III). These items
are used to calculate the nose/eye symptom score,
daily living score, outdoor activity score, sleep
score, physical score, and JRQLQ total score and
were approximately consistent with the items
showing signicant differences when elds ana-
lyzed the scores. The JRQLQ has also been used
to evaluate the efcacy of the drugs for treating
of allergic rhinitis, thereby making an “effective”
judgment if the evaluation of scores for elds
and items shows a signicant reduction13,23. In
an analysis of individual responses of subjects
to the questionnaire, all items whose score was
signicantly lower in the test food group than in
the placebo group had a larger number of subjects
Continuous variables are shown as mean (SD). Values in bold are signicant (p<0.05). 2W, 2 weeks after start of ingestion. 4W,
4 weeks after start of ingestion. SD, standard deviation.
Table VI. Inuence on original QOL questionnaire with VAS expressed for both absolute values and magnitude of change.
Absolute value Magnitude of change
Active Placebo Active Placebo
Variable group group group group
(score) (n = 30 (n = 30) p-value (n = 30 (n = 30) p-value
Itching sensation other than 2W 42.2 (21.3) 35.9 (23.7) 0.06 -3.5 (25.1) -18.0 (24.0) 0.03
ocular/nasal itching sensation 4W 35.6 (26.4) 41.6 (27.8) 0.56 -10.1 (28.5) -12.3 (36.9) 0.80
Blurred vision 2W 47.7 (28.1) 39.8 (25.1) 0.32 -12.3 (27.0) -16.9 (28.3) 0.52
4W 38.7 (25.8) 38.6 (22.8) 0.84 -21.3 (25.6) -18.1 (27.9) 0.65
Rash (skin below the nose, etc.) 2W 28.8 (27.0) 27.2 (25.2) 0.34 -10.1 (26.2) -19.8 (25.2) 0.15
4W 19.6 (22.6) 29.8 (24.5) 0.22 -19.2 (25.5) -17.2 (27.0) 0.77
Difculty in breathing 2W 32.9 (24.2) 34.6 (20.7) 0.96 -14.5 (28.5) -16.7 (23.4) 0.74
4W 26.8 (22.1) 35.6 (24.8) 0.20 -20.6 (24.0) -15.8 (29.3) 0.49
Nasal bleeding 2W 9.3 (19.5) 12.8 (22.1) 1.00 -13.2 (21.3) -17.0 (22.1) 0.49
4W 10.3 (19.0) 10.1 (16.2) 0.62 -12.2 (24.0) -19.7 (26.2) 0.25
Coarse voice 2W 17.7 (22.5) 25.1 (23.2) 0.22 -25.7 (23.2) -20.7 (26.0) 0.43
4W 19.6 (21.1) 27.2 (23.4) 0.20 -23.8 (21.7) -18.6 (31.2) 0.45
Ocular discharge 2W 32.3 (29.7) 34.8 (26.5) 0.73 -19.1 (26.5) -17.2 (29.6) 0.79
4W 26.5 (26.4) 30.2 (23.9) 0.56 -24.9 (22.7) -21.8 (28.9) 0.65
Cough 2W 22.3 (25.2) 27.0 (23.6) 0.44 -26.0 (28.1) -21.9 (30.0) 0.58
4W 22.0 (23.7) 24.4 (23.7) 0.69 -26.3 (24.5) -24.4 (31.5) 0.80
Daytime drowsiness 2W 34.4 (26.5) 40.9 (22.6) 0.33 -21.8 (22.3) -16.8 (30.2) 0.47
4W 31.4 (24.8) 40.4 (21.0) 0.15 -24.8 (22.2) -17.4 (31.4) 0.30
Ocular congestion 2W 38.8 (32.4) 38.3 (25.1) 0.95 -13.3 (27.1) -12.1 (28.5) 0.87
4W 30.3 (31.4) 32.8 (21.5) 0.59 -21.7 (26.9) -17.5 (27.6) 0.55
Throat discomfort 2W 32.6 (25.6) 37.2 (27.4) 0.24 -26.9 (25.6) -16.4 (28.8) 0.14
4W 28.0 (26.7) 37.0 (25.0) 0.09 -31.5 (28.9) -16.5 (30.6) 0.06
Malaise 2W 34.4 (27.0) 37.2 (23.4) 0.74 -21.5 (23.7) -20.6 (29.8) 0.89
4W 25.8 (23.8) 34.6 (24.2) 0.17 -30.1 (19.8) -23.2 (32.0) 0.32
Depth of sleep 2W 38.7 (27.1) 45.5 (29.2) 0.16 -22.0 (18.9) -13.2 (26.6) 0.14
4W 34.5 (26.1) 41.9 (24.1) 0.15 -26.2 (23.9) -16.7 (26.7) 0.15
Ease in falling asleep 2W 36.7 (25.7) 41.7 (27.2) 0.26 -18.6 (20.3) -12.1 (24.5) 0.27
4W 30.5 (24.5) 41.6 (25.9) 0.05 -24.8 (26.6) -12.2 (28.7) 0.08
S. Yamada, M. Shirai, Y. Inaba, T. Takara
4342
answering 0, meaning “absent (no)”, or 1, mean-
ing “mild” in the test food group, indicating that
these changes were clinically signicant. These
results of JRQLQ suggest that ingestion of the
test food reduced the adverse inuence of allergic
rhinitis on QOL, primarily the impact on sleep
and the body.
In severity grading of allergic rhinitis eval-
uated as a secondary outcome, the scores of
“sneezing” (3W and 4W), “rhinorrhea” (1W, 3W,
and 4W), “ocular itching sensation” (1 week af-
ter starting ingestion), and “disturbance in daily
living” (2-4W) were signicantly lower in the
test food group than in the placebo group (Table
IV). Severity grading of allergic rhinitis was con-
ducted by asking each subject to select a concrete
number from a given range reecting the daily
frequency of sneezing and nose-blowing, the
intensity of nasal congestion, and the percentage
of oral breathing15. This is a more subjective
evaluation method than JRQLQ. According to the
criteria for evaluation of the efcacy of treatment
given in the Guidelines for Nasal Allergy Man-
agement, one-level reduction in the severity grade
is deemed as “improved,” and two levels or more
reduction as “markedly improved” or “symptom
disappeared”14. In the present study, the mean
scores of “rhinorrheas” (1W) and “ocular itching
sensation” (1W) were 1.0 (meaning “mild”) in the
test food group and 2.0 (meaning “moderate”) in
the placebo group. This difference by one level
of severity grade between the two groups can be
interpreted as clinically signicant. In the nasal
discharge test, the nasal discharge eosinophil
count at 2W was signicantly lower in the test
food group than in the placebo group (Table V).
Regarding the subjective symptoms related to
sleep, the post-hoc analysis of the responses to
the original questionnaire revealed a signicantly
lower score of “ease in falling asleep” (absolute
value) at 4W in the test food group than in the
placebo group (p=0.049) (Table VI). Thus, in the
evaluation of secondary outcomes, alleviation of
allergy-like symptoms was demonstrated in both
subjective evaluation (severity of allergic rhinitis
and nasal discharge neutrophil count) and subjec-
tive evaluation (primarily disturbances in sleep
and daily living), approximately consistent with
the results from JRQLQ (primary outcomes).
In addition to alleviation of eye/nose symp-
toms mentioned above, the original question-
naire revealed signicant inter-group differences
in the scores of “itching sensation other than
ocular/nasal itching sensation” (absolute value)
and “rash (skin below the nose, etc.)” (absolute
value and magnitude of change) (Table VI). In
the analysis of changes over time of the scores of
“itching sensation other than ocular/nasal itching
sensation” and “rash (skin below the nose, etc.)”
which showed signicant inter-group differences,
the scores tended to decrease constantly in the
test food group. In contrast, the placebo group
showed elevation of the scores at 4W after de-
creasing at 2W. Under the original questionnaire
employed in this study, lower scores indicate bet-
ter subjective ratings. Thus, the test food appears
to have alleviated subjective symptoms through-
out the intervention period.
Quercetin affects the recruitment of immuno-
competent cells to the skin and prevents second-
ary infection outbreaks following the destruction
of the skin barrier4,8. In previous studies8,24,25 in
which healthy adults of both sexes ingested the
same test food as that used in the present study,
containing quercetin in the same quantity or
smaller quantity (100 mg/day), wheal, redness,
skin thickness, and microcirculation after his-
tamine injection was reduced signicantly, sug-
gesting that quercetin also has an immunomod-
ulating activity. Therefore, it seems likely that
in the present study, subjective symptoms, such
as itching sensation and rash, were alleviated by
the effect of quercetin (contained in the test food)
in suppressing the immune reactions in the skin.
Symptoms of allergic rhinitis, both perennial
and seasonal, have been reported to aggravate
QOL, such as sleep, anxiety, and a depressed
mood26. Regarding perennial allergic rhinitis, a
study27 designed to evaluate the inuence on the
score of SF-36 (a questionnaire for evaluation of
health-related QOL) in Japanese patients with pe-
rennial allergic rhinitis demonstrated that among
sneezing, nasal discharge, and nasal congestion,
QOL was most affected by nasal congestion.
Moreover, the inuence of the severity of this
symptom is reportedly greater than that of any
other symptom27. Regarding seasonal allergic
rhinitis, a study28 in Japanese patients with pol-
linosis demonstrated that improved sleep quality
had a signicant positive correlation with nasal
discharge, sneezing, nasal congestion, and nasal/
ocular itching sensation. Also, alleviation in dif-
culty falling asleep had a signicant positive
correlation with ocular itching sensation28. The
present study suggests that if patients with peren-
nial or seasonal allergies orally ingest the querce-
tin-containing test food during the pollen-spread-
ing season, it will help reduce ocular/nasal symp-
Effects of intake of a quercetin-containing supplement on allergic reaction
4343
toms and preserve their QOL. The alleviation
of allergy-like symptoms following ingestion of
the test food probably improved the sleep score
(an indicator of sleep disorder), accompanied by
improvement in QOL, i.e., primarily alleviation
of subjective symptoms, such as decreased think-
ing power, disturbance in outdoor activities, and
malaise. Quercetin combined with the new de-
livery system used in the present study has been
reported10 to have recorded a plasma level after an
oral dose in humans 20-times higher than that of
ordinary quercetin, thanks to the high solubility
and trans-oral absorption. Therefore, an elevation
in the bioavailability of quercetin seems to have
contributed to the alleviation of allergic symp-
toms in the present study. Ingestion of this form
of quercetin was previously shown to alleviate
asthmatic patients’ symptoms and suppress the
inammation following subcutaneous injection
of histamine24,25. The results from the present
study are also consistent with previous ndings8.
In the present study, the intervention was con-
ducted when the pollen-spreading level was prob-
ably higher than usual, and the symptoms of
seasonable allergic rhinitis were more likely to be
induced. Even during such a period, ingestion of
the test food resulted in signicant improvement
in both objective evaluation (severity of allergic
rhinitis and nasal discharge eosinophil count)
and subjective evaluation (primarily inuence
on sleep and body). This allowed us to conrm
that the inuence of allergic rhinitis on QOL can
be signicantly alleviated. However, it was not
possible in the present study to check signicant
changes in unspecic IgE and specic IgE levels
in the blood following test food ingestion. In
a previous study, the nasal discharge IgE level
correlated more closely with the nasal eosinophil
count than with serum IgE level in patients with
Japanese cedar pollinosis29. Serum IgE levels can
elevate in cases complicated by other illnesses,
such as asthma, atopic dermatitis, and parasit-
osis. However, the level of nasal discharge IgE
(formed in the nasal mucosa) is considered to be
less affected by other illnesses29. Furthermore,
lacrimal uid IgE measurement has been used as
a new diagnosis method for allergic conjunctivitis
induced by type I allergy, similarly to allergic
rhinitis2 9,30. Therefore, if IgE contained in nasal
discharge, lacrimal uid, and blood is measured,
we may expect that the test food’s inuence on
antibody formation may be veried.
For safety evaluation, the physical measure-
ment, physical examination, urinalysis, and pe-
ripheral blood test were conducted as the screen-
ing and pre-ingestion test and at 2 and 4 weeks
after starting ingestion. Signicant inter-group
differences were sporadically noted in the phys-
ical measurement parameters, physical examina-
tion, and peripheral blood test. Yet, all these
changes were within the criterion or optimum
range, posing no medical problem31-34 . In inges-
tion, part of the subjects showed values outside
the criterion range. Still, the overall evaluation of
such data and the other data allowed a judgment
that there was no medical problem. In the periph-
eral blood test, the mean of each parameter was
within the criterion range. The subjects showing
some parameters outside the criterion range were
judged to have no medical problem based on
overall evaluation and the data on the other pa-
rameters34-36. Adverse events developed in some
of the subjects, but all events subsided following
oral medication or application of an ophthalmic
solution. They were conrmed to have no causal
relationship to the test food. Thus, the test food
was shown to involve no safety problem.
Conclusions
The present study evaluated the inuence of
4-week continuous ingestion of quercetin-con-
taining test food on subjective symptoms related
to allergic reactions to allergens in Japanese
adults of both sexes having eye and/or nose dis-
comfort. Ingestion of the test food resulted in
signicant improvement in subjective evaluation
(primarily the inuence on sleep and the body)
and objective evaluation (severity of allergic rhi-
nitis and nasal discharge eosinophil count), thus
signicantly alleviating the effect of allergic rhi-
nitis on QOL.
Conflict of Interest
There is no conict of interest which can affect the results
of this study or interpretation of the results among all in-
dividuals involved in this study, their family members, all
contractors, Indena Japan Co., Ltd. and Indena S.p.A.
Acknowledgements
The authors wish to acknowledge Fabio Perversi (Polistudi-
um srl, Milan, Italy), Aashni Shah and Valentina Attanasio
(Polistudium srl, Milan, Italy) for editorial assistance. Ed-
itorial assistance was supported by Indena S.p.A. The au-
thors also wish to acknowledge Honyaku Center Inc. for
providing the Japanese-English translation.
S. Yamada, M. Shirai, Y. Inaba, T. Takara
4344
Funding
This study was conducted under assignment from Inde-
na Japan Co., Ltd. and Indena S.p.A. at the cost of the as-
signors.
Availability of Data and Material
Data will be available upon reasonable request.
Authors’ Contribution
All authors contributed equally and gave their approval to
submit.
Ethics Approval
The study protocol was approved on 19 November 2019
by the Medical Cor poration Seishinkai, Takara Clinic
(Approval No. 1911-1911-IJ01-01-TC) and registered with
UMIC-CTR (UMIN000038765) on 3 December 2019. It
was carried out under sufcient consideration of human
rights, safety and well-being of individual participants in
accordance with the Declaration of Helsinki, the Clinical
Study Act, and the Clinical Study Act Enforcement Reg ula-
tions. Written informed consent was obtained from all sub-
jects before enrollment in the study.
Trial Registered Number
UMIN-CTR000038765.
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