Quercetin reduces illness but not immune perturbations after intensive exercise.

Abstract

To investigate the effects of quercetin supplementation on incidence of upper respiratory tract infections (URTI) and exercise-induced changes in immune function.
Trained male cyclists (N=40) were randomized to quercetin (N=20) or placebo (N=20) groups and, under double-blind procedures, received 3 wk quercetin (1000 mg.d(-1)) or placebo before, during, and for 2 wk after a 3-d period in which subjects cycled for 3 h.d(-1) at approximately 57% Wmax. Blood and saliva samples were collected before and after each of the three exercise sessions and assayed for natural killer cell activity (NKCA), PHA-stimulated lymphocyte proliferation (PHA-LP), polymorphonuclear oxidative-burst activity (POBA), and salivary IgA output (sIgA).
Pre- to postexercise changes in NKCA, PHA-LP, POBA, and sIgA did not differ significantly between quercetin and placebo groups. URTI incidence during the 2-wk postexercise period differed significantly between groups (quercetin=1/20 vs placebo=9/20, Kaplan-Meier analysis statistic=8.31, P=0.004).
Quercetin versus placebo ingestion did not alter exercise-induced changes in several measures of immune function, but it significantly reduced URTI incidence in cyclists during the 2-wk period after intensified exercise.

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7
Quercetin Reduces Illness but Not Immune
Perturbations after Intensive Exercise
DAVID C. NIEMAN1, DRU A. HENSON1, SARAH J. GROSS1, DAVID P. JENKINS1, J. MARK DAVIS2,
E. ANGELA MURPHY2, MARTIN D. CARMICHAEL2, CHARLES L. DUMKE1, ALAN C. UTTER1,
STEVEN R. MCANULTY1, LISA S. MCANULTY1, and EUGENE P. MAYER2
1Departments of Health, Leisure, and Exercise Science; Biology; and Family and Consumer Sciences; Appalachian
State University, Boone, NC; and2Department of Exercise Science, University of South Carolina, Columbia, SC
ABSTRACT
NIEMAN, D. C., D. A. HENSON, S. J. GROSS, D. P. JENKINS, J. M. DAVIS, E. A. MURPHY, M. D. CARMICHAEL, C. L.
DUMKE, A. C. UTTER, S. R. MCANULTY, L. S. MCANULTY, and E. P. MAYER. Quercetin Reduces Illness but Not Immune
Perturbations after Intensive Exercise. Med. Sci. Sports Exerc., Vol. 39, No. 9, pp. 1561–1569, 2007. Purpose: To investigate the effects
of quercetin supplementation on incidence of upper respiratory tract infections (URTI) and exercise-induced changes in immune
function. Methods: Trained male cyclists (N = 40) were randomized to quercetin (N = 20) or placebo (N = 20) groups and, under
double-blind procedures, received 3 wk quercetin (1000 mgIdj1) or placebo before, during, and for 2 wk after a 3-d period in which
subjects cycled for 3 hIdj1at approximately 57% Wmax. Blood and saliva samples were collected before and after each of the three
exercise sessions and assayed for natural killer cell activity (NKCA), PHA-stimulated lymphocyte proliferation (PHA-LP),
polymorphonuclear oxidative-burst activity (POBA), and salivary IgA output (sIgA). Results: Pre- to postexercise changes in NKCA,
PHA-LP, POBA, and sIgA did not differ significantly between quercetin and placebo groups. URTI incidence during the 2-wk
postexercise period differed significantly between groups (quercetin = 1/20 vs placebo = 9/20, Kaplan–Meier analysis statistic = 8.31,
P = 0.004). Conclusion: Quercetin versus placebo ingestion did not alter exercise-induced changes in several measures of immune
function, but it significantly reduced URTI incidence in cyclists during the 2-wk period after intensified exercise. Key Words:
CYCLING, NATURAL KILLER CELLS, T LYMPHOCYTES, NEUTROPHILS, SALIVARY IgA
T
body compartments (12,23–26). These exercise-induced
immune changes occur at the same time the human body
is experiencing oxidative stress, inflammation, muscle
microtrauma, and suppressed function against foreign
pathogens (3,24).
The influence of several nutritional countermeasures to
exercise-induced immune alterations have been investigated
including carbohydrate beverages, omega-3 fatty acids,
zinc, glutamine, bovine colostrum, and various types of
antioxidants such as vitamins C and E (22,25,26,28,31). Of
these, carbohydrate ingestion has proven most effective
against outcome measures related to inflammation, with
he physiologic stress induced by prolonged and
intensive exertion is reflected in transient yet
significant immune system perturbations in multiple
little effect on exercise-induced downturns in T and natural
killer (NK) cell function and other aspects of immunity such
as salivary IgA output (22).
Polyphenolic compounds are abundant throughout the
plant kingdom and are found in a wide variety of human
foods. The flavonoids, which are the best defined group of
polyphenols in the human diet, comprise a largeand complex
group, all of which contain a three-ring structure with two
aromatic centers and a central oxygenated heterocycle
(17,18). The physiologic effects of dietary flavonols such
as quercetin are of great current interest for their antioxi-
dative, antiinflammatory, antipathogenic, cardioprotective,
and anticarcinogenic activities (4,9,14,19,21).
Flavonol consumption by U.S. adults is approximately
20–35 mgIdj1, with quercetin contributing three fourths of
this amount (18,27). Significant food sources include
apples, onions, berries, leafy green vegetables, hot peppers,
red grapes, and black tea (17,18). Quercetin accumulates
in the outer and aerial tissues (skin and leaves) because
biosynthesis is stimulated by light (17). Human subjects
can absorb significant amounts of quercetin glycosides
(the predominant form in plant foods) (10,18,32). Quercetin
exists primarily in conjugated forms in human plasma, with
only trace amounts as aglycone (17,18). Elimination of
quercetin metabolites is quite slow, with reported half-lives
of 11–28 h and a primary elimination route as CO2
Address for correspondence: David C. Nieman, DrPH, FACSM, Dept
HLES, PO Box 32071, Appalachian State University, Boone, NC 28608;
E-mail: niemandc@appstate.edu.
Submitted for publication March 2007.
Accepted for publication April 2007.
0195-9131/07/3909-1561/0
MEDICINE & SCIENCE IN SPORTS & EXERCISE?
Copyright ? 2007 by the American College of Sports Medicine
DOI: 10.1249/mss.0b013e318076b566
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7
(16,18,32). Long-term feeding of quercetin in rats leads to
an accumulation of quercetin in several different organs,
particularly the lungs, testes, kidney, heart, liver, thymus,
and muscle (8).
Quercetin possesses antioxidant, free radical–scavenging,
and antiinflammatory properties that may influence immune
system competence and resistance to pathogens, although
most data come from in vitro and animal experiments
(1,5,20). Such experiments suggest that quercetin increases
neutrophil chemotaxis and respiratory-burst activity, macro-
phage phagocytosis, NK cell lytic activity, and mitogen-
stimulated lymphocyte proliferation (1,11,20,21). Quercetin
regulates the expression of some genes including tran-
scription factor nuclear factor-kappa B (NF6B), and may
thus attenuate induction of cytokine transcription for
interleukin (IL)-1A, tumor necrosis factor (TNF)->, mono-
cyte chemoattractant protein (MCP), and macrophage
inflammatory protein (MIP) (3,6,21).
Quercetin in culture with target cells and pathogens
exerts antipathogenic activities against a wide variety of
viruses and bacteria (7). For example, several culture
studies showed that quercetin reduced infectivity of target
cells and replication at an early stage for herpes simplex
viruses (HSV)-1 and -2, adenoviruses (ADV) -3, -8, and -11,
and coronavirus (5,9). Other culture studies show that
various quercetin conjugates reduced human immunodefi-
ciency (HIV), rhinovirus, and severe acute respiratory
syndrome (SARS) virus replication through various path-
ways, including reduced lipase activity, binding of viral
capsid proteins, and inhibition of DNA gyrase and proteases
(4,7,9). Quercetin`s antiviral effects may also be mediated
through induction of interferon (20). When cultured with
human peripheral blood mononuclear cells (PBMC), quer-
cetin induces the gene expression and production of helper
T lymphocyte-1 (Th-1)-derived interferon gamma (IFNF),
and it downregulates Th-2 derived IL-4 (20).
No published human studies exist regarding the influence
of quercetin ingestion on exercise-induced immune dysfunc-
tion. One study showed that 6 wk of quercetin supplementa-
tion improved 30-km time-trial performance by 3.1% in 11
male cyclists, and the authors speculate that the performance
advantage with quercetin use may have been related to an
attenuation of oxidative stress and muscle IL-6 release (15).
Given quercetin`s antioxidant, free radical–scavenging,
and antiinflammatory properties, and its potential to
influence immune function and inhibit infectivity and
replication of a broad spectrum of viruses, we hypothesized
that quercetin compared with placebo ingestion would
attenuate immune dysfunction and counter the risk of
upper–respiratory tract infection (URTI) in endurance
athletes engaging in repeated and sustained heavy exertion.
METHODS
Subjects. Forty trained male cyclists were recruited as
experimental subjects through local and collegiate cycling
clubs. Written informed consent was obtained from each
subject, and the experimental procedures were approved
by the institutional review board of Appalachian State
University.
Research design. Two to three weeks before the
first test session, subjects reported to the ASU human
performance lab for orientation and measurement of body
composition and cardiorespiratory fitness. Bodycomposition
was assessed by hydrostatic weighing using an electronic
load cell system (Exertech, Dresbach, MN) (29). V˙O2max
was determined using a graded maximal protocol (25-W
increase every 2 min, starting at 150 W), with the subjects
using their own bicycles on CompuTrainer Pro Model
8001 trainers (RaceMate, Seattle, WA). Oxygen uptake and
ventilation were measured using the MedGraphics CPX
metabolic system (MedGraphics Corporation, St. Paul,
MN). Heart rate was measured using a chest heart rate
monitor (Polar Electro Inc., Woodbury, NY). Basic
demographic and training data were obtained through a
questionnaire.
Subjects agreed to avoid the use of large-dose vitamin/
mineral supplements (above 100% of recommended dietary
allowances), nutritional supplements, ergogenic aids, herbs,
and medications known to affect immune function for 3 wk
before, during, and 2 wk after the 3-d period of intensified
exercise. Subjects were asked to train normally during both
the 3-wk period preceding and the 2-wk period after
intensified exercise. During orientation, a dietitian
instructed the subjects to follow a diet moderate in
carbohydrate (using a food list) during the 3 wk before
and during the 3-d test sessions. Subjects recorded food
intake in a 3-d food record before the first exercise test
session. The food records were analyzed using a com-
puterized dietary assessment program (Food Processor,
ESHA Research, Salem, OR).
The cyclists were randomized to quercetin (N = 20) or
placebo (N = 20) groups. Under double-blind procedures,
subjects received quercetin (1000 mgIdj1) or placebo
supplements for 3 wk before, during, and 2 wk after the
3-d period of intensified exercise. Tang powder and 500 mg
of pure quercetin powder (QU995, Quercegen Pharma,
Newton, MA) were mixed with powdered food coloring
and placed in plastic vials. Subjects mixed the contents of
the vials with 8 ounces of water in green plastic bottles, and
they consumed the beverage before their first and last meals
of each day to achieve an intake of 1000 mgIdj1of quer-
cetin. Subjects returned empty vials to the study dietitian to
verify compliance with the supplementation regimen.
Subjects came to the lab for three consecutive days after
the 3-wk quercetin or placebo supplementation period.
Subjects cycled for 3 h at approximately 57% Wmax, or
57% of the maximal watts attained during graded maximal
protocol. Subjects reported to the lab at 2:00 p.m. having
not ingested energy in any form after 12:30 p.m. Blood
samples were collected about 30 min before exercise and
about 15 min after exercise. Subjects ingested 0.5–1.0 L of
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7
water per hour during the 3-h cycling bout, with no other
beverages or food ingested during the test sessions.
During the test sessions, experimental subjects cycled
using their own bicycles on CompuTrainer Pro Model 8001
trainers (RaceMate, Seattle, WA) with the exercise load set
at approximately 57% Wmax. Metabolic measurements were
made every 30 min of cycling using the MedGraphics CPX
metabolic system to verify workload.
Blood cell counts, hormones. Blood samples were
drawn from an antecubital vein with subjects in the
supine position. Routine complete blood counts (CBC)
were performed by our clinical hematology laboratory,
and provided leukocyte subset counts, hemoglobin, and
hematocrit. Other blood samples were centrifuged in
sodium heparin or EDTA tubes, with plasma aliquoted
and then stored at j80-C. Plasma concentrations of
cortisol were determined using competitive solid-phase
125I radioimmunoassay (RIA) technique (Diagnostic
Products Corporation, Los Angeles, CA) with cortisol-
specific Ab-coated tubes (Coat-A-Count tubes). Intraassay
(CV intra) and interassay (CV inter) coefficients of
variation were 4.5 and 5%, respectively. Assay sensitivity
was 5.5 nM (0.2 KgIdLj1). For plasma epinephrine and
norepinephrine, blood samples were drawn into chilled
tubes containing EGTA and glutathione, centrifuged, and
the plasma was stored at j80-C until analysis. Plasma
concentrations of epinephrine and norepinephrine were
determined by competitive enzyme immunoassay (EIA)
(Labor Diagnostika Nord, Nordhorn, Germany) using the
microtiter plate format. CV intra and CV inter for
epinephrine and norepinephrine were 11 and 14%, and
16 and 15%, respectively. Sensitivity of the epinephrine
and norepinephrine assays for plasma samples are 11 and
44 pgImLj1, respectively.
Plasma quercetin. Total plasma quercetin (quercetin
and its primary conjugates) was measured after solid-phase
extraction via reverse-phase HPLC, with UV detection as
described by Quercegen Pharma (Newton, MA, personal
communication, April 2006). This procedure is similar to
that previously published by Ishii et al. (13). Quercetin
conjugates were hydrolyzed by incubating 250- to 500-KL
plasma aliquots with 10 KL of 10% DL-dithiothreitol
(DTT) solution, 50 KL of 0.58 M acetic acid, 50 KL of a
mixture of A-glucuronidase and arylsulfatase, and crude
extract from Helix pomatia (Roche Diagnostics GmbH,
Mannheim, Germany) for 40 min at 37-C. After incubation,
500 KL of 0.01 M oxalic acid was added, and then each
sample was vortexed and centrifuged for 5 min at 10000
rpm. One milliliter of supernatants was then applied to
solid-phase extraction cartridges (Oasis HLB, 1 mL, 30 mg,
SPE cartridge; Waters Corporation, Milford, MA) that were
preconditioned with 1 mL of methanol (MeOH), 0.5 mL of
0.01 M oxalic acid, and 1 mL of dH2O, and drawn through
at a rate of 0.5 mLIminj1using a vacuum manifold (Waters
Corp., Milford, MA). Cartridges were then washed with 0.5
mL of MeOH ? 2. Eluant was collected into 1.5-mL
microcentrifuge tubes. Ten microliters of 10% DTT solution
was added to the combined eluant, and the samples were
then vortexed for 1 min and placed into a vacuum
concentrator (Savant Speed Vac SC 110 Savant Instruments
Inc., Farmindale, NY) until MeOH was completely
evaporated. The residue was reconstituted with 150 KL of
MeOH/dH2O (1/1). Fifty-microliter injections were used for
HPLC analysis.
Chromatographic analysis was performed using a Waters
Breeze system (Waters Corporation, Milford, MA) consist-
ing of a Waters 1525 binary HPLC pump, 2487 UV
detector, and symmetry C18, 5-Km, 4.6 ? 150-mm column.
The analysis data were acquired and processed using Breeze
software (v. 3.02). A mixture of acetonitrile with 0.1%
formic acid (A) and dH2O with 0.1% formic acid (B) was
used as the mobile phase. The gradient elution was
programmed as follows: 0–1.5 min, 10/90% A/B; 1.5–9.5
min, 40/60% A/B; 9.5–11.5 min, 90/10% A/B; 11.5–15
min, 10/90% A/B. The column temperature was maintained
at 30-C. The flow rate was 1.0 mLIminj1. Quantitation of
the quercetin peak was based on the standard addition
method, using both plasma and MeOH, with similar results.
Both standards and samples were treated in an identical
manner.
Lymphocyte subsets. The proportions of T cells
(CD3+) and NK cells (CD3–CD56+) were determined in
whole-blood preparations, and absolute numbers were
calculated using the CBC data to allow group comparison
on counts of circulating cells. For lymphocyte preservation,
1 mL of whole blood collected in EDTAwas added to 1 mL
of Cyto-Chex reagent (Streck Laboratories, Omaha, NE).
Cyto-Chex reagent is a solution that is formulated to
preserve the white blood cells in blood samples without
reducing the activity of the antigenic sites. Samples treated
with Cyto-Chex can be maintained for 7 d before processing
and analysis by flow cytometric methods. Lymphocyte
phenotyping was accomplished by one- or two-color
fluorescent labeling of cell-surface antigens with mouse
antihuman monoclonal antibodies (CD3/CD56, CD19) and
isotype control, conjugated to fluorescein isothiocyanate
(FITC)orphycoerythrinderivative(RD-1)(BeckmanCoulter,
Fullerton, CA). Briefly, 100 KL of EDTA-anticoagulated
whole blood was incubated with 10 KL of monoclonal
antibodies for 10 min at room temperature in 12 ? 75-mm
polypropylene tubes. After incubation, the sample was
processed on a Q prep Instrument (Beckman Coulter,
Fullerton, CA) using ImmunoPrep Reagent (Beckman
Coulter, Fullerton, CA). This allows for erythrocyte lysis,
as well as stabilizing and fixing of the lymphocytes in one
step without the trauma of mixing, vortexing, and
centrifuging of samples. Samples were analyzed on a
Beckman Coulter Epics XL-MCL flow cytometer using
forward and side scatter; a total of 5000 events were counted
in each reaction tube.
NK cell activity. NK cell activity (NKCA) was assessed
using a modification of a flow cytometry assay (2).
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7
Peripheral blood mononuclear cells (effector cells, 3.75 ?
106cells per milliliter) were isolated from heparinized
blood by density gradient centrifugation with Ficoll-
Hypaque. K562 target cells (1 ? 106cells per milliliter)
were labeled for 20 min with DiO reagent (0.01 mL of 3
mM DIOC18 (3), 3,3µ-dioctadecyloxacarbocyanine
perchlorate (DiO) (Sigma Chemical Company, St. Louis,
MO) in DMSO per milliliter of cell suspension) washed and
resuspended to a concentration of 5 ? 105cells per
milliliter. Effector cells and target cells were added to
individual tubes (0.9-mL final volume) to yield E:T ratios of
60:1, 30:1, 15:1, 7.5:1, 3.8:1, and 1.9:1. All tubes received
0.1 mL of a 500-KgImLj1solution of propidium iodide (PI)
(Sigma Chemical Company, St. Louis, MO). The tubes
were vortexed, and the cells were pelleted by centrifugation
for 15 s, then incubated for 2 h at 37-C in a 5% CO2
incubator. At the end of the incubation, the tubes were
vortexed and placed on ice, and the cells were analyzed on a
flow cytometer within 30 min. DiO-labeled target-cell
membranes emit a green fluorescence (FL1), and PI-labeled
compromised cells emit a red fluorescence (FL3). The
percentage of target (green) cells that were also
compromised (red) was determined. Control tubes received
target cells and PI alone, and effector cells and PI alone.
The results were acceptable if the percentage of
compromised cells in these controls was G 5%. Plots of
the percentage of compromised target cells at the various
E:T ratios were constructed, and linear regression analysis
was performed. The results are expressed as percent lysis of
DiO-stained K562 cells at a 20:1 E:T ratio.
PHA-stimulated lymphocyte proliferation. The
mitogenic response of lymphocytes was determined in
whole-blood culture using phytohemagglutinin (PHA) at
optimal and suboptimal doses, which were previously
determined by titration experiments. Heparinized venous
blood was diluted 1:10 with complete media consisting of
RPMI-1640 supplemented with 5% heat-inactivated fetal
bovine serum, penicillin, streptomycin, sodium pyruvate,
L-glutamine, A-2-mercaptoethanol, and Mito+ serum
extender (Becton Dickinson Immunocytometry Systems,
San Jose, CA). PHA was prepared in RPMI-1640 media at
a concentration of 1 mgImLj1and then further diluted with
complete media to the optimal and suboptimal working
concentrations (25 and 12.5 KgImLj1, respectively). A
100-KL aliquot of the diluted blood was dispensed into each
of triplicate wells of a 96-well flat-bottom microtiter plate. To
each well, 100 KL of the appropriate mitogen dose was
added. Control wells received complete media instead of
mitogen. After a 72-h incubation at 37-C and 5% CO2, the
cells were pulsed with 1 KCi of thymidine (methyl)-3H (New
England Nuclear, Boston, MA) prepared with RPMI-1640.
After pulsing, cells were incubated for an additional 4 h
before harvesting. The radionucleotide incorporation was
assessed by a Wallac 1209 RackBeta Liquid Scintillation
Counter (Gaithersburg, MD), with the results expressed as
experimental minus control counts per minute (cpm).
Whole-blood polymorphonuclear oxidative-
burst activity assay. For each sample, 100 KL of
whole blood was dispensed into two 12 ? 75-mm tubes
labeled 1 and 2. Twenty five microliters of working
dihydrorhodamine 123 (DHF-123) solution (Sigma Chemical
Company, St. Louis, MO) was added to each of tubes 1
(endogenous respiratory-burst activity) and 2 (stimulated
respiratory-burst activity). The DHF-123 was prepared
from a stock solution of 5 mgImLj1as follows: 10 KL of
the stock solution was added to 990 KL of a 1:1 ratio of
phosphatebufferedsalineandglucose.Thefinalconcentration
of DHF-123 was 1 KgImLj1. The tubes were incubated at
37-C for 15 min. After the incubation period, 10 KL of the
working phorbol 12-myristate 13-acetate (PMA) solution
(Sigma Chemical Company, St. Louis, MO) was added to
tube 2. The PMA was prepared from a stock solution of
1 mgImLj1, and 10 KL of the stock solution was added to
990 KL of a 1:1 ratio of phosphate-buffered saline and
glucose. The final concentration of PMAwas 100 ngImLj1.
Tubes were incubated again for 15 min at 37-C. After the
incubation period, the tubes were placed on ice. Samples
were processed on a Q prep instrument (Beckman Coulter,
Fullerton, CA) using ImmunoPrep Reagent (Beckman
Coulter, Fullerton, CA). This allowed for erythrocyte lysis,
as well as stabilizing and fixing of the blood cells in
one step without the trauma of mixing, vortexing, and
centrifuging of samples. Samples were analyzed on a
Beckman Coulter Epics XL-MCL flow cytometer, using
forward scatter and side scatter, and were gated on
granulocytes. A total of 5000 cells were counted in each
reaction tube. The mean channel number for the fluorescence
peaks was determined, and the polymorphonuclear (PMN)
oxidative-burst activity was calculated by subtracting the
mean channel number of the endogenous respiratory-burst
activity from the mean channel number of the stimulated
respiratory-burst activity.
Plasma myeloperoxidase. An enzyme-linked
immunoassay was used to measure plasma myelo-
peroxidase (MPO) protein levels in accordance with
instructions from the manufacturer (Bioxytech, Oxis
International, Inc., Portland, OR). CV intra and CV inter
variations for MPO were 3.45 and 7.76%, respectively.
Salivary IgA. Unstimulated saliva was collected for four
minutes by expectoration into 15-mL plastic, sterilized vials.
Participants were urged to pass as much saliva as possible
into the vials during the 4-min timed session. The saliva
TABLE 1. Subject characteristics (mean T SE).
Cyclers (N = 20)
Quercetin
Cyclers (N = 20)
PlaceboP Value
Age (yr)
Body mass (kg)
Body fat (%)
Training (kmIwkj1)
V˙O2max(mLIkgj1Iminj1)
Maximal power (W)
HRmax(bpm)
V˙O2, volume of oxygen consumption; HR, heart rate.
26.1 T 1.8
74.7 T 0.2
13.8 T 1.2
242 T 27
53.2 T 1.2
314 T 9
188 T 1
29.1 T 2.4
74.2 T 1.4
11.5 T 0.6
270 T 29
54.7 T 1.1
320 T 69
190 T 2
0.321
0.846
0.094
0.493
0.365
0.554
0.328
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samples were centrifuged for 5 min at 200g, then frozen in
dry ice after collection and stored at j80-C until analysis.
Saliva volume was measured to the nearest 0.1 mL, and
saliva total protein was quantified using the Coomassie
protein assay reagent, a modification of the Bradford
Coomassie dye binding colorimetric method. Salivary IgA
(sIgA) was measured by enzyme linked immunosorbent
assay according to the procedures of the Hunter Immunology
Unit (Royal Newcastle Hospital, Newcastle, Australia) (24).
The data were expressed as sIgA secretion rate (KgIminj1).
CV intra and CV inter variation for sIgA concentration were
4.92 and 9.26%, respectively.
Illness logs. Subjects filled in a health log during the
5-wk supplementation period, listing codes for symptoms of
upper–respiratory tract infection (URTI). The following
health codes were recorded daily, in accordance with
previous investigations by our research team (24): 1) no
health problems today; 2) sick with cold symptoms (runny,
stuffy nose, sore throat, coughing, sneezing, colored
discharge); 3) sick with flu symptoms (fever, headache,
general aches and pains, fatigue and weakness, chest
discomfort, cough); 4) sick, with nausea, vomiting, and/or
diarrhea; 5) muscle, joint, or bone problems/injury; 6)
allergy symptoms; 7) other health problems (describe). An
URTI episode was recorded if cold or flu symptoms
persisted for 2 d or longer.
Statistical analysis. Data are expressed as mean T SE.
Data in Tables 1 and 2 were compared between groups
using Student`s t-tests. Data in Tables 3 and 4, and Figures
1 through 5, were analyzed using a 2 (groups) ? 6 (time
points) repeated-measures ANOVA. For certain variables of
interest, an overall day effect was calculated that compared
changes across the 3 d of measurement. When Box`s M
suggested that the assumptions necessary for the univariate
approach were not tenable, the multivariate approach to
repeated-measures ANOVA was used (Pillais trace). When
interaction effects were significant (P e 0.05), pre- to
postexercise changes were calculated and compared between
quercetin and placebo groups using Student`s t-tests, with
significance set at a P e 0.05. Upper–respiratory tract
infection incidence rates (Fig. 6) were compared between
groups using a Kaplan–Meier analysis.
RESULTS
Subject characteristics for the 40 cyclists randomized to
quercetin and placebo groups are summarized in Table 1.
No significant differences were found between groups for
age, body composition, training history, or maximal
performance measures. Subjects in the quercetin and
placebo groups came into the study averaging approximately
1.5 T 0.2 and 1.6 T 0.2 h of cycling per training bout.
Thus, the 3-d intensified exercise period (9 h of exercise)
represented nearly a doubling of their normal exercise work-
load. Three-day food records before the 3-d exercise period
revealed no significant group differences in energy or
macronutrient intake (data not shown), and for all subjects
combined, energy intake was 2684 T 117 kcalIdj1, with
carbohydrate representing 56.6 T 2.5%, protein 16.2 T 0.8%,
and fat 27.2 T 1.8%. A poststudy questionnaire revealed
that nine subjects in each group guessed they were on
quercetin, four in each group guessed placebo, and seven in
each group were uncertain (thus, there were no significant
group differences).
Performance data in Table 2 reveal that subjects in
quercetin and placebo groups were able to maintain a mean
power output of approximately 57% Wmaxat an oxygen
TABLE 2. Performance data—average of three 3-h cycling bouts (mean T SE).
Quercetin (N = 20)Placebo (N = 20)P Value
Power (W)
Power (% Wmax)
Heart rate (bpm)
Heart rate (% HRmax)
V˙O2max(mLIkgj1Iminj1)
V˙O2(% V˙O2max)
Cadence (rpm)
178 T 5
56.8 T 0.2
149 T 2
79.4 T 0.8
36.0 T 0.9
67.8 T 0.8
80.8 T 2.2
181 T 4
56.5 T 0.3
149 T 3
78.1 T 1.0
36.9 T 0.8
67.6 T 1.1
83.7 T 2.2
0.626
0.486
0.897
0.300
0.458
0.919
0.349
TABLE 3. Pre- to postexercise (3-h cycling bouts at approximately 57% Wmax) changes in blood leukocyte subset counts in quercetin compared with placebo groups during a 3-d
period (mean T SE).
Quercetin (N = 20) Placebo (N = 20)
P Values:
Time; 2 ? 6 InteractionPrePostPrePost
Granulocytes (109Lj1)
Day 1
Day 2
Day 3
Total lymphocytes (109Lj1)
Day 1
Day 2
Day 3
T cells (109Lj1)
Day 1
Day 2
Day 3
Natural killer cells (109Lj1)
Day 1
Day 2
Day 3
3.40 T 0.22
3.80 T 0.27
3.19 T 0.22
12.2 T 0.8
9.82 T 0.59
8.22 T 0.53
3.17 T 0.21
3.18 T 0.16
2.79 T 0.17
11.4 T 1.0
8.99 T 0.57
7.02 T 0.40
G 0.001; 0.870
1.89 T 0.15
1.90 T 0.13
1.89 T 0.13
2.52 T 0.23
2.59 T 0.22
2.38 T 0.16
1.80 T 0.11
1.79 T 0.13
1.72 T 0.10
2.16 T 0.15
2.36 T 0.21
2.09 T 0.13
G 0.001; 0.561
1.08 T 0.09
1.20 T 0.10
1.19 T 0.10
1.52 T 0.13
1.62 T 0.15
1.51 T 0.11
1.14 T 0.07
1.20 T 0.09
1.12 T 0.07
1.38 T 0.09
1.54 T 0.12
1.37 T 0.09
G 0.001; 0.365
0.38 T 0.09
0.22 T 0.04
0.28 T 0.05
0.37 T 0.07
0.24 T 0.04
0.24 T 0.04
0.29 T 0.04
0.18 T 0.02
0.21 T 0.02
0.27 T 0.04
0.21 T 0.03
0.17 T 0.02
G 0.001; 0.794
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7
consumption of approximately 68% V˙O2maxand a cadence
slightly above 80 rpm. Plasma volume change using
hemoglobin and hematocrit data did not differ between
groups during the three exercise bouts and averaged less
than 1% because of ingestion of 0.5–1.0 L water per hour of
exercise (data not shown). After 3 wk of supplementation,
plasma quercetin levels for the quercetin and placebo
groups were 1158 T 218 and 113 T 30 KgILj1, respectively
(P G 0.001).
Group comparisons of all preexercise data on day 1 (i.e.,
resting-state values after 3 wk of supplementation), shown
in Tables 3 and 4 and Figures 1–5, show no significant
differences. Significant main time effects were measured for
blood leukocyte subset counts, and plasma cortisol, epi-
nephrine, and norepinephrine, with no quercetin compared
with placebo group differences, as outlined in Tables 3 and
4. The magnitude of postexercise increases for blood
granulocyte counts, total lymphocyte counts, NK cell
counts, plasma cortisol, plasma epinephrine, and plasma
norepinephrine diminished across the 3-d period (day effect
for all variables, P G 0.05). NK cell lytic activity decreased
from pre- to postexercise during each of the 3-h cycling
bouts (Fig. 1) (and across the 3-d period, P G 0.001), with
no group differences [time effect, P G 0.001; 2 (group) ? 6
(time) interaction effect, P = 0.632]. PHA-stimulated
lymphocyte proliferation increased (in parallel with the
increase in blood T cell counts) after exercise during each
cycling bout (Fig. 2), with no group differences (time effect,
P G 0.001; interaction effect, P = 0.804). Polymorphonu-
clear respiratory-burst activity decreased after each cycling
bout (and across the 3-d period, P G 0.001) (Fig. 3), with no
group differences (time effect, P G 0.001; interaction effect,
P = 0.938). Plasma myeloperoxidase increased after each
cycling bout (Fig. 4), with no group differences (time effect,
P G 0.001; interaction effect, P = 0.328). Salivary IgA
output tended to decrease over time (P = 0.044), but not
after exercise (Fig. 5), with no group differences (inter-
action effect, P = 0.920).
Figure 6 summarizes the upper–respiratory tract infection
data during the entire supplementation period (5 wk and
3 d). Infection rates did not differ during the initial 21-d
period, but they were significantly different during the 14-d
period after the 3 d of intensified exercise (quercetin group
incidence = 1/20; placebo group incidence = 9/20; Kaplan–
Meier analysis, log–rank test statistic = 8.31, P = 0.004).
DISCUSSION
Cyclists randomized to 1000 mgIdj1of pure quercetin
compared with placebo under double-blinded methods had
higher plasma quercetin levels after 3 wk of supplementa-
tion (9.2-fold difference) and experienced a markedly lower
incidence of URTI symptoms during the 2-wk period after
TABLE 4. Pre- to postexercise (3-h cycling bouts at approximately 57% Wmax) changes in plasma cortisol, epinephrine, and norepinephrine in quercetin compared with placebo
groups during a 3-d period (mean T SE).
Quercetin (N = 20)Placebo (N = 20)
P Values: Time; 2 ? 6 Interaction PrePostPre Post
Cortisol (nM)
Day 1
Day 2
Day 3
Epinephrine (nM)
Day 1
Day 2
Day 3
Norepinephrine (nM)
Day 1
Day 2
Day 3
139 T 10
100 T 8
96 T 7
230 T 19
217 T 17
190 T 17
113 T 8
82 T 5
91 T 6
253 T 22
185 T 19
158 T 16
G 0.001; 0.151
0.41 T 0.05
0.25 T 0.04
0.28 T 0.04
0.91 T 0.12
0.50 T 0.07
0.55 T 0.06
0.37 T 0.07
0.19 T 0.03
0.19 T 0.05
0.84 T 0.16
0.54 T 0.11
0.44 T 0.07
G 0.001; 0.899
2.70 T 0.22
2.83 T 0.23
2.99 T 0.21
6.69 T 0.58
5.99 T 0.40
5.85 T 0.46
2.70 T 0.25
3.02 T 0.25
3.28 T 0.30
5.85 T 0.39
5.90 T 0.65
4.79 T 0.48
G 0.001; 0.110
FIGURE 1—Natural killer (NK) cell lytic activity before and after 3 h
of cycling at 57% Wmaxin quercetin (N = 20) and placebo (N = 20)
groups during three consecutive days. Main time effect, P G 0.001;
group ? time interaction effect, P = 0.632.
FIGURE 2—PHA-stimulated lymphocyte proliferation before and
after 3 h of cycling at 57% Wmaxin quercetin (N = 20) and placebo
(N = 20) groups during three consecutive days. Main time effect, P G
0.001; group ? time interaction effect, P = 0.804.
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7
intensified exercise. Group differences in illness rates
occurred despite comparable measures of immune function
taken before and after exercise during a 3-d period of
intensified exercise after 3 wk of supplementation. We
collected data during February and March of 2006, a period
when illness rates are typically high across university
campuses. This time period, combined with the unusual
physiologic stress the subjects experienced (9 h of intense
exercise during a 3-d period, combined with nearly 1 L of
blood sampling), help explain the high illness rate in the
placebo group.
Thus, quercetin may have reduced URTI rates using
direct antipathogenic pathways. A growing literature base
supports the antipathogenic capacities of quercetin when
cultured with target cells and a broad spectrum of pathogens
including URTI-related rhinoviruses, adenoviruses, and
coronaviruses (4,5,7,9). These studies indicate that querce-
tin blocks viral replication at an early stage of multiplication
using several mechanisms, including inhibition of proteases
by molecular docking, binding of viral capsid proteins, and
suppression of virulence enzymes such as DNA gyrase and
cellular lipase (4,5,7). We are unaware of any other human
clinical trials demonstrating the efficacy of quercetin
compared with placebo in reducing URTI incidence, and
this is the first investigation to show that quercetin supple-
ments lower illness rates in athletes during periods of
intensified training and elevated URTI risk. Thus, further
research is warranted to explore quercetin`s antipathogenic
capacities under varying human conditions.
Acute changes in immune measures experienced by the
cyclists included previously reported increases in neutrophil
and T cell counts, MPO, and mitogen-stimulated lympho-
cyte proliferation, and decreases in NK cell lytic activity
and PMN respiratory-burst activity (12,22–26,28,31). The
magnitude of postexercise increases for blood granulocyte,
total lymphocyte, and NK cell counts, plasma stress
hormone levels, NK cell lytic activity, and PMN respiratory-
burst activity diminished significantly across the 3-d period.
This occurred despite maintenance of the same exercise
workload and intensity for each 3-h bout of cycling. Suzuki
et al. (30) also have noted some attenuation of exercise-
induced neutrophilia and neutrophil oxidative activity in
subjects cycling at 90 W for 90 min, 3 d in a row. Our data
suggest that trained cyclists adapt quickly to the physiologic
stress of repeated bouts of intense and prolonged exercise, and
FIGURE 3—Polymorphonuclear respiratory-burst activity before and
after 3 h of cycling at 57% Wmaxin quercetin (N = 20) and placebo
(N = 20) groups during three consecutive days. Main time effect,
P G 0.001; group ? time interaction effect, P = 0.938.
FIGURE 4—Plasma myeloperoxidase concentrations before and after
3 h of cycling at 57% Wmaxin quercetin (N = 20) and placebo (N = 20)
groups during three consecutive days. Main time effect, P G 0.001;
group ? time interaction effect, P = 0.328.
FIGURE 5—Salivary IgA output before and after 3 h of cycling at
57% Wmaxin quercetin (N = 20) and placebo (N = 20) groups during
three consecutive days. Main time effect, P G 0.001; group ? time
interaction effect, P = 0.920.
FIGURE 6—Upper–respiratory tract infection rates did not differ
during the initial 21-d period between groups, but they were
significantly different during the 14-d period after the 3 d of intensified
exercise(quercetin group incidence = 1/20; placebo group incidence =
9/20; Kaplan–Meier analysis, log–rank test statistic = 8.31, P =
0.004).
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7
by the second and third bout they experience lower levels of
stress hormones and diminished immune perturbations.
We and others have previously shown that carbohydrate
compared with placebo beverage ingestion during pro-
longed and intensive exertion attenuates increases in
neutrophil counts, but it has little or no effect on the other
immune measures included in this study (for review, see
Nieman and Bishop (22)). Other nutritional interventions
with athletes have had inconsistent or null effects
(22,25,26,28,31).
Published reports of quercetin`s effects on immune
function, oxidative stress, and inflammation led us to
hypothesize that this flavonol would attenuate exercise-
induced immune dysfunction (6,11,14,20,21), but our data
do not support this hypothesis, at least within the context of
this study. Prior studies, however, have used in vitro and
animal models to test quercetin`s influence on immune
function, some with unusually high levels of quercetin. For
example, rats fed 100 mgIkgj1of quercetin daily for 7 wk
had significantly enhanced NK cell activity compared with
controls (11). Human peripheral blood mononuclear cells
cultured with quercetin at concentrations ranging between 1
and 50 KM for 24–96 h significantly inhibited TNF->
production and gene expression in T cells and monocytes
(21). Consumption of polyphenol-rich cereals by prema-
turely aging mice significantly enhanced macrophage
phagocytosis, microbicidal activity, NKCA, and lympho-
cyte proliferation compared with controls, with most of
these immune benefits linked by the investigators to
quercetin (1). Our data indicate that quercetin did not alter
resting immunity or act as a countermeasure to exercise-
induced immune changes, underscoring the difficulty and,
hence, caution that should be used in applying in vitro and
animal data to human investigations.
In summary, 3 wk of 1000 mgIdj1of pure quercetin
compared with placebo ingestion in cyclists led to marked
differences in rates of illness (5 vs 45%, respectively)
during the 2-wk period after intensified exercise. URTI
incidence differed between groups despite no measurable
influence of quercetin on multiple measures of immune
function taken before and after 3 h of exercise. These data
support in vitro observations that quercetin supplements
may reduce illness rates after periods of heavy training by
athletes through direct antipathogenic mechanisms.
Partially supported by a grant from the Defense Advanced
Research Projects Agency (DARPA) and the Army Research Office
(ARO), award number W911NF-06-0014.
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