ValtrexTM Therapy for Epstein-Barr Virus Reactivation and Upper Respiratory Symptoms in Elite Runners
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ValtrexTM Therapy for Epstein-Barr Virus
Reactivation and Upper Respiratory
Symptoms in Elite Runners
AMANDA J. COX1, MAREE GLEESON1,2, DAVID B. PYNE3, PHILO U. SAUNDERS3,
ROBERT L. CLANCY1,2, and PETER A. FRICKER4
1
School of Biomedical Sciences, Faculty of Health, University of Newcastle, Callaghan, NSW, AUSTRALIA; 2Immunology,
Hunter Area Pathology Service, John Hunter Hospital, New Lambton, NSW, AUSTRALIA; and 3Departments of
Physiology and 4Technical Direction, Australian Institute of Sport, Canberra, ACT, AUSTRALIA
ABSTRACT
COX, A. J., M. GLEESON, D. B. PYNE, P. U. SAUNDERS, R. L. CLANCY, and P. A. FRICKER. ValtrexTM Therapy for
Epstein-Barr Virus Reactivation and Upper Respiratory Symptoms in Elite Runners. Med. Sci. Sports Exerc., Vol. 36, No. 7, pp.
1104 –1110, 2004. Purpose: The aim of the study was to examine the effectiveness of prophylactic administration of the antiviral agent
ValtrexTM for control of Epstein-Barr virus (EBV) reactivation and upper respiratory symptoms in elite distance runners. Methods:
Twenty elite male distance runners were randomized into a 4-month double-blind, placebo-controlled cross-over trial. Saliva samples
were collected weekly and mucosal immune status assessed by measurement of secretory IgA (SIgA) using an enzyme-linked
immunosorbent assay (ELISA). EBV reactivation was monitored at the same time by detection of EBV in saliva using a quantitative
real-time polymerase chain reaction. The initial EBV status of the runners was determined by detecting EBV antibodies in serum using
an ELISA. Upper respiratory symptoms were recorded using self-reporting illness logs. Results: There was no evidence of any marked
change in maximal oxygen uptake (P ⫽ 0.86), training volume (P ⫽ 0.30), or mucosal immunity (P ⫽ 0.21) over the study period.
ValtrexTM treatment resulted in an 82% reduction in the detectable EBV load in saliva for EBV seropositive runners compared with
the placebo treatment (P ⫽ 0.04). The incidence of upper respiratory symptoms was not reduced by ValtrexTM treatment. Conclusions:
The prophylactic administration of ValtrexTM reduced EBV reactivation but was not an effective intervention strategy for limiting upper
respiratory symptoms in this cohort of elite distance runners. The upper respiratory symptoms in the distance runners could not be
directly attributed to infection and may be of a noninfectious inflammatory nature. Key Words: EPSTEIN BARR VIRUS, DISTANCE
RUNNERS, RESPIRATORY ILLNESS, SALIVA, SECRETORY IMMUNOGLOBULIN A
U
pper respiratory tract infection (URTI) is the most There are a number of conflicting reports regarding the
common reported infectious illness in both the gen- incidence of URTI in high-performance athletes and con-
eral population and elite athletes (14,16), account- troversy exists whether symptoms are truly the result of
ing for 30 – 40% of visits to sports medicine clinics (19). infection. A retrospective analysis of athlete medical records
Reported cases of URTI are predominantly of viral origin for high performance swimmers over a 10-yr period (5)
and self-limiting, with symptoms obvious 1–2 d after infec- failed to find significant differences between rates of URTI
tion and persisting for up to 2 wk (5,16). Athletes exhibiting in the swimmers (2.7 episodes per year) and age- and
symptomatic URTI frequently present with sore throat and sex-matched general population (2.4 episodes per year) (4).
nasal congestion, and may experience headache, enlarged In contrast, several epidemiological studies dependent on
lymph nodes, fever, malaise, and myalgia (5,16). URTI are self-reported upper respiratory symptoms (URS) have re-
of particular concern to both elite and high-performance ported an increased incidence of URTI among high perfor-
athletes because of the potential to disrupt training sched- mance athletes, compared with low-moderate exercising
ules and competition performance (14). groups (19,22), particularly after the completion of intense
endurance competition (22). This increased risk of URTI
among high-performance groups has been attributed to per-
Address for correspondence: Maree Gleeson, Director of Immunology, turbations in immune function after intense exercise (11,19),
Hunter Area Pathology Service, Locked Bag 1, Hunter Region Mail Cen- placing athletes at an increased risk of contracting infections
tre, NSW, 2310, Australia; E-mail: maree.gleeson@hunter.health.nsw. in the postexercise recovery period (15,23). However, a
gov.au. direct association of URTI with immune suppression has
Submitted for publication June 2003. only been found for secretory IgA (SIgA), with decreased
Accepted for publication March 2004.
levels in saliva after periods of intense exercise (9) and over
0195-9131/04/3607-1104 extended training seasons (8,9).
MEDICINE & SCIENCE IN SPORTS & EXERCISE® Nonprimary Epstein-Barr virus (EBV) infection has been
Copyright © 2004 by the American College of Sports Medicine proposed as a possible cause of URS in high-performance
DOI: 10.1249/01.MSS.0000131957.40985.2B athletes (10). EBV, a member of the herpes group of viruses,
1104TABLE 1. The study consisted of four treatment phases, each of 1 month, in which salivary SIgA, EBV excretion, incidence of upper respiratory illness, patterns of training, and
running performance were assessed; subjects were assigned to either Valtrex™ or the placebo in treatment 1 (month 2) and crossed-over to the opposing treatment arm in
treatment 2 (month 4).
Baseline Treatment 1 Washout Treatment 2
Month 1 Month 2 Month 3 Month 4
Daily illness log 3 3 3 3
Daily training diary 3 3 3 3
Weekly measurement of SIgA 3 3 3 3
Weekly detection of EBV 3 3 3 3
Monthly performance assessment 3 3 3 3
Daily Valtrex™ or placebo 3 3
is transmitted in saliva (28) and infects both epithelial cells MATERIALS AND METHODS
and resting B lymphocytes of the oropharynx (25), estab-
lishing lifelong virus persistence (3,25). EBV has been Subjects. Twenty elite male distance runners, aged
detected in the saliva of healthy, seropositive individuals 18.8 –29.7 yr (mean age 24.6 yr, SD 3.0 yr) were recruited
(3,26), with stable levels of EBV-specific antibodies re- from scholarship holders at the Australian Institute of Sport
ported years after the primary infection (26). Both cellular (AIS) or nationally ranked distance runners. The runners
and antibody-mediated immune mechanisms are activated competed in distances ranging from 800 m to marathon
in response to initial EBV infection (28), facilitating the (42.2 km). The study was approved by the ethics committees
neutralization of extracellular virus particles and the de- of the University of Newcastle, Hunter Area Health Service
struction of infected B lymphocytes (28). The transient and the Australian Institute of Sport. Written informed con-
immunosuppression associated with intense exercise has the sent was obtained from all subjects.
potential to generate window periods in which the regula- Study design. The study was conducted during the
tion of EBV-infected cells is likely to be diminished. As southern hemisphere winter. Runners were randomized into
such, high-performance athletes may experience an in- a double-blind, placebo-controlled, cross-over trial consist-
creased risk of EBV reactivation. Occurring in the orophar- ing of a baseline month and two treatment months separated
ynx, the cell damage and inflammation associated with this by a washout month (Table 1). In each of the treatment
process of reactivation has the potential to induce URS months, half of the runners received ValtrexTM (Glaxo
typical of those noted in elite athletes after intense training Wellcome Australia Limited, VIC, Australia) and half a
or competition. placebo containing glucose (Capital Chem-Mart, Lyneham,
Nonprimary EBV infection results from the reactivation ACT, Australia). ValtrexTM was administered at a dose of
of prior EBV-infected cells and involves an increased pro- 500 mg orally, twice daily, with a similar dose of glucose
duction of EBV particles and their shedding into saliva (26). employed for the placebo. Throughout the study, partici-
This phenomenon has been reported in response to physical pants were required to provide resting saliva samples at
and psychological stressors including spaceflight (21), aca- weekly intervals to allow monitoring of SIgA levels and
demic stress (12), and loneliness (12) and has been identi- EBV excretion. A daily illness log was used to monitor
fied as a significant cause of oropharyngitis in teenagers upper respiratory symptoms experienced by the runners.
(27). The clinical presentations of the teenagers with EBV Training patterns were monitored by the use of daily train-
reactivation were noted to be similar to those in athletes
ing logs.
reporting URS (10), and it was hypothesized that the URS
Athletic performance. Athletic fitness was assessed at
frequently reported by high-performance athletes around
the commencement and completion of the study by incre-
times of increased physical and psychological stress could
mental treadmill testing to volitional exhaustion and the
be associated with the reactivation of prior EBV infection.
determination of maximal oxygen consumption (V̇O2max)
This hypothesis was examined in a cohort of elite swim-
by using a custom built treadmill and open-circuit indirect
mers, which found that EBV reactivation was associated
with 55% of episodes of URS and occurred during periods calorimetry system (AIS, Belconnen, ACT, Australia). All
of mucosal immune suppression (10). tests were completed in the AIS Department of Physiology
The aim of this study was to determine whether the Laboratory under standard conditions, including tempera-
prophylactic administration of an antiviral agent could arrest ture (20 –22°C), pressure (700 –715 mm Hg), and relative
EBV replication and shedding of the virus into saliva, lead- humidity (30 –35%). Before commencement of each test,
ing to attenuation of the subsequent associated URS in elite subjects were weighed to the nearest 0.1 kg using digital
distance runners. The antiviral agent acyclovir prevents the weighing scales (Teraoka Seiko Co. Ltd., Tokyo, Japan) to
replication of herpes group viruses and is commonly pre- allow for reporting of oxygen consumption relative to body
scribed for the treatment of herpes infections, and adminis- mass. The V̇O2max test protocol involved running at a speed
tration in patients suffering primary EBV infection reduces of 18 km·h⫺1 with incremental increases of 1 km·h⫺1 every
viral shedding in saliva (1). The antiviral agent selected for minute to 20 km·h⫺1. The gradient of the treadmill was then
this study was ValtrexTM, the pro-drug of acyclovir, which increased by 1% every minute until volitional exhaustion
has greater efficacy in control of EBV (6). allowing the determination of V̇O2max.
EBV AND RESPIRATORY ILLNESS IN ELITE RUNNERS Medicine & Science in Sports & Exercise姞 1105EBV serology. EBV serology testing, indicative of concentration of 100 nM, and 2 L of the extraction solu-
present or past infection with EBV, was conducted at re- tion from saliva samples. Amplification and detection were
cruitment. Whole blood samples were collected from the performed with a ABI Prism 7700 Sequence Detection
antecubital vein into evacuated collection tubes (Vacuette, System with Sequence Detection v1.7 Software (PE Applied
Greiner Bio-one, Kremsmunster, Austria) by using standard Biosystems) under the universal thermal cycling conditions:
venipuncture techniques. Serum was separated by centrifu- 2 min at 50°C to allow optimal uracil-N-glycosylase activ-
gation at 4000 rpm for 5 min. The detection of IgM and IgG ity, 10 min at 95°C to activate the AmpliTaq Gold DNA
antibodies for EBV viral-capsid and nuclear antigen was Polymerase, and 40 cycles of 15 s at 95°C and 1 min at 60°C.
completed with commercial ELISA kits (Pan Bio, Windsor, Accumulation of the fluorogenic reporter dye was mon-
QLD, Australia) using tetramethylbenzidine as the colori- itored by the ABI Prism sequence detector and a threshold
metric substrate. All samples were analyzed in duplicate cycle (CT) determined for each sample from the PCR cycle
using a Behring ELISA Processor III Immunoanalyser number at which the fluorescence exceeded a threshold limit
(Dade Behring Diagnostics, Marburg, Germany). (set at 10 times the SD of the baseline fluorescence calcu-
Illness records. The runners completed a prospective lated over PCR cycles 3–10). All samples were analyzed in
illness log designed at the AIS and previously used by AIS duplicate and were categorized negative for the presence of
athletes (9) to record the presence and degree of severity of EBV-DNA if the mean CT value exceeded 36. Quantitative
any symptomatic illnesses. Any doctor’s visits and medica- analysis of EBV load was undertaken using the pGEM-
tions, including vitamin or dietary supplements, taken dur- BALF5 plasmid DNA obtained from Kimura et al. (13). A
ing the study were recorded. The study medical officer standard curve of CT values for serial dilutions of the plas-
assessed all reports of URS to exclude any unrelated respi- mid DNA was generated, and the CT values of each sample
ratory illnesses (e.g., allergy) and to determine the duration were extrapolated to the respective EBV copy number.
of each episode. A pair of extraction controls from saliva samples previ-
Salivary IgA concentrations. Whole-mixed saliva ously characterized as positive and negative for the presence
was collected by passive drool directly into collection tubes. of EBV was included in each analysis. PCR controls in-
Samples were collected 2 h postprandially and before the cluded a no-template control, extraction solutions from sa-
late afternoon exercise session on the same day of each liva samples collected from a patient with no history of EBV
week to minimize the possible influence of diurnal rhythms. infection, from a patient with recent diagnosis of primary
All samples were frozen immediately after collection and EBV infection, and an EBV culture from the EBV-produc-
were stored at ⫺80°C until analysis. SIgA concentrations in ing monkey cell line B95-8 (American Type Culture Col-
saliva were measured using an in-house ELISA assay as lection, Rockville, MD). The between-run variances for the
previously described by Gleeson et al. (7). All samples were positive control and EBV culture were 4% and 5%,
assayed in triplicate in conjunction with high, moderate, and respectively.
low positive controls and saliva from an IgA-deficient in- Statistical analysis. All data analysis was completed
dividual as a negative control. SIgA concentrations were using the statistical software package Statistics/Data Anal-
determined by standardization against Human Serum Pro- ysis™ (STATA), Version 6.0 (Stata Corporation, Texas).
tein Calibrator (Dako, Glostrup, Denmark) referenced Athletic performance and training volumes were stable
against BCR CRM470. The between-run variances for the across the study period and were not considered confound-
high, moderate, and low positive controls were 10%, 14%, ing variables in the analysis of SIgA concentrations or
and 15%, respectively. patterns of URS. The monthly mean SIgA concentrations,
Quantitative analysis of EBV excretion in saliva. the total number of days of URS, and the mean duration of
EBV excretion was monitored by the detection of EBV- episodes of URS for the cohort were compared across the
DNA in saliva samples using a quantitative real-time poly- four study months using a repeated measures ANOVA.
merase chain reaction (RT-PCR). DNA was isolated from SIgA concentrations and EBV copy number estimates were
saliva samples using a Wizard Genomic DNA Purification log transformed for the ANOVA. A Pearson’s correlation
Kit (Promega, Madison, WI) with minor modifications to was used to assess the degree of association between SIgA
manufacturer’s instructions as previously described by concentration and the number of episodes URS. The signif-
Gleeson et al. (10). Commercially available EBV-specific icance level for all tests was set at P ⬍ 0.05. It was
primers and a fluorogenic probe (PE Applied Biosystems, determined that a 50% reduction in EBV excretion was
Foster City, CA) were used in the RT-PCR to amplify a necessary if a statistical power of 80% was to be maintained.
region of the BALF5 gene, as previously described (13).
The forward and reverse primers and the fluorogenic probe
RESULTS
had the sequences 5'-CGGAAGCCCTCTGGACTTC-3', 5'-
CCCTGTTTATCCGATGGAATG-3' and 5'-TGTACACG- Epstein Barr-virus serology. Sixteen of the runners
CACGCACGAGAAATGCGCC-3', respectively. A 25-L (75%) were positive for previous infection with EBV, based
final volume PCR was completed by using 12.5 L of a on the detection of anti-EBNA IgG antibodies in the serum
double-strength TaqMan PCR Universal Master Mix (PE and EBV in saliva. No runner had detectable levels of
Applied Biosystems), BALF5 specific primers at a final anti-VCA IgM antibodies in their serum, indicating that
concentration of 300 nM, a BALF5-specific probe at a final none of the cohort had current primary EBV infection.
1106 Official Journal of the American College of Sports Medicine http://www.acsm-msse.orgTABLE 2. Patterns of upper respiratory symptoms (URS) reported by runners for each of the study months.
Baseline Placebo Washout Valtrex™
Measures of URS Month Month Month Month
No. URS episodes 12 6 1 11
% all URS episodes 40 20 3 37
No. subjects reporting URS 8/25 5/20 1/20 11/21
% subjects reporting URS 32 25 5 52
Total number of symptom days* 50 39 28 72
Mean days URS per episode† 6 5 7 7
Range of URS days per 1–24 2–14 N/A 3–15
episodes†
* Total number of symptom days is the number of days of reported URS for all subjects in each month.
† Mean days URS per episode attributes all days of URS to the month in which the symptoms were first reported.
Patterns of training and performance. The mean Patterns of salivary IgA. The overall weekly mean
training volume for the cohort was 102 km·wk⫺1 (95% CI: SIgA concentration for the cohort during the study was 57.8
88 –107 km·wk⫺1) and did not vary significantly across the mg·L⫺1 (95% CI: 51.8 – 64.4 mg·L⫺1). Within subjects, the
study. The mean V̇O2max for the cohort at the commence- mean variability in weekly SIgA concentrations was 7%
ment of the study was 69.7 mL·kg⫺1·min⫺1 (95% CI: 67.1– (range: 3–12%). The weekly variability in SIgA concentra-
72.3 mL·kg⫺1·min⫺1) and was not significantly different tions between-subjects was also 7%. The monthly mean
(P ⫽ 0.86) from the mean V̇O2max at the completion of the SIgA concentration did not vary significantly over the
study (mean ⫽ 69.5 mL·kg⫺1·min⫺1; 95% CI: 65.9 –73.0 course of the study (P ⫽ 0.21) (Fig. 1). There were no
mL·kg⫺1·min⫺1). significant differences in the monthly mean SIgA concen-
Patterns of upper respiratory illness. During the trations between the EBV seropositive and seronegative
study period, 15 subjects (75%) experienced at least one epi- subjects (P ⫽ 0.26). There was a trend for lower SIgA
sode of URS consistent with symptoms of URTI. The mean concentrations among subjects reporting URS during each
number of episodes per subject over the 4 months was 1.9 month (mean: 51.3 mg·L⫺1; 95% CI: 47.7–55.3 mg·L⫺1)
(range: 1–5). and the mean number of days of symptoms over compared with those who did not report URS (mean: 57.4
the 4 months was 12 d (range: 2–51). More runners reported mg·L⫺1; 95% CI: 50.2– 65.7 mg·L⫺1); however, although
URS during the ValtrexTM treatment month (52%) than any this did not reach statistical significance (P ⫽ 0.08), there is
other month (Table 2). However, there were no significant a possibility that these differences (Fig. 2) are clinically
differences across the four study months for the number of days relevant (9).
of symptoms reported (P ⫽ 0.98) nor for the mean duration of Epstein-Barr virus excretion in saliva. Of the 16
episodes of URS (P ⫽ 0.32). There were no significant dif- EBV-seropositive subjects, 12 (75%) completed both the
ferences in the proportion of EBV seropositive and EBV se- ValtrexTM and placebo treatment months. Five EBV sero-
ronegative subjects reporting URS (P ⫽ 0.36). positive subjects had no detectable levels of EBV in any
saliva sample collected throughout the study. The propor-
tion of subjects and samples with detectable levels of EBV
was consistent across the baseline, placebo, and washout
months (Table 3). In the ValtrexTM treatment month only
FIGURE 1—Monthly mean salivary IgA concentrations for each study
month are represented as box and whisker plots. The concentrations
between the 25th and 75th percentiles are boxed and the median value
is indicated within the box. The 5th to 95th range of concentrations is FIGURE 2—Monthly mean SIgA concentrations for subjects with and
indicated by the bars and any outlying values are plotted as single without reported episodes of upper respiratory symptoms (URS) in
points. each month over the study period.
EBV AND RESPIRATORY ILLNESS IN ELITE RUNNERS Medicine & Science in Sports & Exercise姞 1107TABLE 3. Patterns of Epstein-Barr virus (EBV) excretion for the EBV seropositive subjects are provided for each treatment month; the proportion of subjects with EBV detected in
saliva, the proportion of saliva samples collected with EBV detected, and the monthly mean EBV copy number during each treatment month.
Baseline Placebo Washout Valtrex™
Measures of EBV Reactivation Month Month Month Month
% of subjects with detectable EBV 40 (6/15) 33 (4/12) 33 (4/12) 8 (1/13)
% of saliva samples positive for EBV 16 (12/75) 18 (8/44) 17 (7/41) 4 (2/50)
Monthly mean EBV copy no. 108.9 79.8 23.1 14.3
Range of mean copy no. 25.5–1022.5 18.9–528.5 8.9–79.0 —
two saliva samples, from one subject, had detectable levels of confirm ValtrexTM as an effective antiviral agent for
EBV. The monthly mean EBV viral load was highest in the control of EBV. However, the study failed to demonstrate
baseline month at (106.3 copies·L⫺1) and was lowest in the prophylactic ValtrexTM administration as an effective
ValtrexTM treatment month (14.0 copies·L⫺1) (Fig. 3). The intervention for reducing URS in this cohort of elite
mean EBV load was 82% lower in the ValtrexTM treatment runners.
month compared with the placebo month (P ⫽ 0.04). The reactivation of EBV, and the detection of EBV in
Associations with EBV excretion. Temporal rela- saliva, has been reported in a variety of groups exposed to
tionships between EBV excretion and the appearance of physical and environmental stressors including 79 –100% of
URS could not be fully characterized from the current study Antarctic winter expeditioners (17), 91% of astronauts dur-
due to the small number of saliva samples with detectable ing preparation for spaceflight (21), and 64% of EBV se-
EBV. EBV excretion was associated with reports of URS in ropositive elite swimmers during intense training (10). Cy-
the same week on only two occasions (7% of all reported
totoxic T (TC) cells have been identified as responsible for
URS episodes). EBV excretion in the week before the re-
the control of EBV infected B lymphocytes (21). TC cell
ported appearance of URS occurred only once (4% of all
function has been reported to be disrupted in response to
reported URS episodes).
physiological stress (16), allowing reactivation and excre-
tion of EBV in the oropharynx and offering one possible
DISCUSSION mechanism for the high level of EBV detection among these
This study demonstrated a significant reduction in EBV groups. Athletes may be at particular risk of EBV reactiva-
excretion into saliva in response to the prophylactic admin- tion as studies have demonstrated that intense exercise re-
istration of ValtrexTM to elite distance runners during rou- duces the number of circulating TC lymphocytes (2,20).
tine high volume training. Only one subject had detectable However, the consistent SIgA concentrations observed in
EBV excretion during ValtrexTM treatment. The mean viral this cohort of elite distance runners during the study indi-
load in this subject, as well as in the overall study cohort, cates that the training programs did not adversely affect their
was significantly lower during the ValtrexTM treatment mucosal immune function over the study period. The ab-
month compared with the levels in the nontreatment months. sence of any substantial mucosal immune suppression may
The EBV viral load in the washout month between treat- have reduced the likelihood of EBV reactivation in this
ments was lower compared with the baseline and placebo cohort, and could explain the lower frequency of EBV
months, suggesting a possible carry-over effect of ValtrexTM detected than had been anticipated from the earlier investi-
treatment beyond 1 month in those who had received gation of elite swimmers (10).
ValtrexTM as the first arm of the study. The results The previous study of elite swimmers had indicated a
temporal relationship between the excretion of EBV in
saliva at times of mucosal immune suppression and the
subsequent appearance of URS (10). It was anticipated that
reducing EBV excretion through the prophylactic adminis-
tration of ValtrexTM would result in a reduction in URS in
the EBV seropositive subjects during the ValtrexTM treat-
ment month. However, the converse was observed and the
proportion of the EBV seropositive subgroup reporting URS
was highest during the ValtrexTM treatment month. In this
cohort of distance runners, there was no significant temporal
relationship between EBV excretion and the appearance of
URS, suggesting that etiological agents other than EBV
were the likely cause of the URS. If infections other than
EBV were responsible for the URS in the current study,
ValtrexTM, an antiviral agent with specific actions against
the herpes group of viruses only, would not be effective in
FIGURE 3—The monthly mean Epstein-Barr virus (EBV) viral load
(copy number) detected in the saliva samples collected from EBV reducing the incidence of URS. However, the absence of a
seropositive runners during each of the study months. mucosal immune response during episodes of URS also
1108 Official Journal of the American College of Sports Medicine http://www.acsm-msse.orgindicates that the URS were unlikely to be related to an ported by evidence of increased plasma concentrations of
infectious cause. the pro-inflammatory cytokines interleukin-1 (IL-1) and
Similar to the report by Heath et al. (11), findings from interleukin-6 (IL-6) after intense exercise (18). Further
this study infer that elite distance runners may experience a support for URS in runners resulting from of an inflam-
higher incidence of URS than elite athletes participating in matory process can be found from the findings of a
other sports. Calculation of an annual incidence of URS double-blind, placebo-controlled trial conducted by
from this study conducted during the winter months must be Schwellnus et al. (24) in a group of competitive male
viewed with caution but the average incidence of 1.9 epi- distance runners. Schwellnus et al. found that the use of
sodes of URS per person over 4 months equates to an annual the topical antiinflammatory FusafungineTM during a 9-d
incidence of 5.7 episodes. This incidence is higher than the period after a 58-km ultra-marathon event was able to
2.4 episodes of URTI per year reported for the age-related reduce the incidence of URS.
Australian general population (4) and the 2.7 episodes per This study highlights that investigations of URS and
year reported for elite swimmers training at the same sport- therapeutic interventions are sport specific and conclu-
ing institute (5). The increased incidence of URS in the elite sions drawn for one sport cannot be universally applied to
distance runners may be related to the nature of the athletic all sports or groups of athletes. However, in EBV sero-
sport. Distance runners undertaking prolonged and intensive positive athletes suffering recurrent URS and with evi-
exercise ventilate large volumes of air through the respira- dence of immunosuppression, therapeutic intervention
tory tract which may lead to mucosal drying, increased with ValtrexTM may be worthy of consideration. Further
exposure to airborne particles, and localized inflammation investigations are needed of the inflammatory processes
(15). Several groups have suggested that drying of the after intense exercise and any association with the ap-
mucosal surfaces of the upper airways contributes to the pearance of URS.
transient mucosal immunosuppression observed after in-
tense exercise, through a reduced secretion of SIgA onto The participation of the runners in this study and their coaches is
mucosal surfaces (14,15). Although mucosal SIgA suppres- gratefully appreciated. The authors also wish to acknowledge the
sion was not observed in this cohort, it is possible that assistance of Ms. Sharron Hall (Hunter Area Pathology Service) with
the salivary IgA ELISA and Ms. Keida Watson, Ms. Lindy Rose, Dr.
mucosal drying, causing physical damage to the mucosal Cliff Meldrum (Hunter Area Pathology Service), and Dr. Terry Grissel
surface and a subsequent inflammatory response, was per- (University of Newcastle) for their assistance with establishing the
ceived by the athletes as symptomatic of URTI. real-time PCR assay.
This research was funded by collaborative research grants from
The possibility of inflammation contributing to the the University of Newcastle (Australia) and the Australian Institute of
incidence of URS in the elite distance runners is sup- Sport.
REFERENCES
1. ANDERSSON, J., B. SKOLDENBERG, W. HENLE, et al. Acyclovir treat- 10. GLEESON, M., D. PYNE, J. AUSTIN, et al. Epstein-Barr virus reacti-
ment in infectious mononucleosis: a clinical and virological study. vation and upper respiratory illness in elite swimmers. Med. Sci.
Infection 15:S14 –S20, 1987. Sports Exerc. 34:411– 417, 2002.
2. BERK, L. S., D. C. NIEMAN, W. S. YOUNGBERG, et al. The effect of 11. HEATH, G. W., E. S. FORD, T. E. CRAVEN, C. A. MACERA, K. L.
long endurance running on natural killer cells in marathoners. JACKSON, and R. R. PATE. Exercise and the incidence of upper
Med. Sci. Sports Exerc. 22:207–212, 1990. respiratory tract infections. Med. Sci. Sports Exerc. 23:152–157,
3. CRUCHLEY, A. T., D. M. WILLIAMS, G. NIEDOBITEK, and L. S. 1991.
YOUNG. Epstein-Barr virus: biology and disease. Oral Diseases 12. KIECOLT-GLASER, J., C. SPEICHER, J. HOLLIDAY, and R. GLASER.
3:S156 –S163, 1997. Stress and the transformation of lymphocytes by Epstein-Barr
4. DOUGLAS, R. M., and T. C. MUIRHEAD. A Study of the Social, virus. J. Behav. Med. 7:1–12, 1984.
Psychological and Environmental Factors Associated with Respi- 13. KIMURA, H., M. MORITA, Y. YABUTA, et al. Quantitative analysis of
ratory Infections amongst Australians. Adelaide, Australia: Uni- Epstein-Barr virus load by using a real-time PCR assay. J. Clin.
versity of Adelaide, Department of Community Medicine, 1978, Microbiol. 37:132–136, 1999.
pp. 1– 49. 14. MACKINNON, L. T. Exercise and resistance to infectious illness. In:
5. FRICKER, P. A., M. GLEESON, A. FLANAGAN, D. PYNE, W. MC- Advances in Exercise Immunology, L. T. Mackinnon (Ed.). Cham-
DONALD, and R. L. CLANCY. A clinical snapshot: do elite swimmers paign, IL: Human Kinetics, 1999, pp. 1–26.
experience more upper respiratory illness than nonathletes? Clin. 15. MACKINNON, L. T. Immunity in athletes. Int. J. Sports Med. 18:
Exerc. Physiol. 2:155–158, 2000. S62–S68, 1997.
6. GLAXOWELLCOME. Valaciclovir Product Monograph. Boronia: Gl- 16. MCDONALD, W. Upper respiratory tract infections. In: Medical
axoWellcome Australia Limited, 1998, pp. 1–50. Problems in Athletes, F. B. Fields and P. A. Fricker (Eds.).
7. GLEESON, M., J. L. FRANCIS, D. J. LUGG, et al. One year in Ant- Malden, MA: Blackwell Science, 1997, pp. 6 –10.
arctica: mucosal immunity at three Australian stations. Immunol. 17. MEHTA, S. K., D. L. PIERSON, H. COOLEY, R. DUBOW, and D. LUGG.
Cell Biol. 78:616 – 622, 2000. Epstein-Barr virus reactivation associated with diminished cell-
8. GLEESON, M., W. MCDONALD, A. W. CRIPPS, D. B. PYNE, R. L. mediated immunity in Antarctic expeditioners. J. Med.Virol. 61:
CLANCY, and P. A. FRICKER. The effect on immunity of long-term 235–240, 2000.
intensive training in elite swimmers. Clin. Exp. Immunol. 102: 18. MOLDOVEANU, A. I., R. J. SHEPHARD, and P. N. SHEK. The cytokine
210 –216, 1995. response to physical activity and training. Sports Med. 31:115–
9. GLEESON, M., W. A. MCDONALD, D. B. PYNE, et al. Salivary IgA 144, 2001.
levels and infection risk in elite swimmers. Med. Sci. Sports Exerc. 19. NIEMAN, D. C. Exercise, upper respiratory tract infection, and the
31:67–73, 1999. immune system. Med. Sci. Sports Exerc. 26:128 –139, 1994.
EBV AND RESPIRATORY ILLNESS IN ELITE RUNNERS Medicine & Science in Sports & Exercise姞 110920. NIEMAN, D. C., A. R. MILLER, D. A. HENSON, et al. Effect of high- (URTI) in runners after a 58-km race. Med. Sci. Sports Exerc.
versus moderate-intensity exercise on lymphocyte subpopulations 29:S296, 1997.
and proliferation response. Int. J. Sports Med. 15:199 –206, 1994. 25. SIXBEY, J. W., J. G. NEDRUD, N. RAAB-TRAUB, R. A. HANES, and
21. PAYNE, D. A., S. K. MEHTA, S. K. TYRING, R. P. STOWE, and D. L. J. S. PAGANO. Epstein-Barr virus replication in oropharyngeal
PIERSON. Incidence of Epstein-Barr virus in astronaut saliva during epithelial cells. N. Engl. J. Med. 310:1225–1230, 1984.
spaceflight. Aviat. Space Environ. Med. 70:1211–1213, 1999. 26. YAO, Q. Y., A. B. RICKINSON, and M. A. EPSTEIN. A re-examination
22. PETERS, E. M., J. M. GOETZSCHE, B. GROBBELAAR, and T. D. of the Epstein-Barr virus carrier state in healthy seropositive
NOAKES. Vitamin C supplementation reduces the incidence of individuals. Int. J. Cancer 35:35– 42, 1985.
postrace symptoms and upper respiratory-tract infection in ultra- 27. YODA, K., T. SATA, T. KURATA, and H. ARAMAKI. Oropharyn-
marathon runners. Am. J. Clin. Nutr. 57:170 –174, 1993. gotonsillitis associated with non-primary Epstein-Barr virus
23. PETERS-FUTRE, E. M. Vitamin C, neutrophil function and upper infection. Arch. Otolaryngol. Head Neck Surg. 126:185–193,
respiratory tract infection risk in distance runners: the missing 2000.
link. Exerc. Immunol. Review. 3:32–52, 1996. 28. YOUNG, L. S. Epstein-Barr virus (Herpesviridae). In: Encyclopedia
24. SCHWELLNUS, M., M. KIESSIG, W. DERMAN, and T. NOAKES. Fusa- of Virology, A. Granoff and R. Webster (Eds.). San Diego: Aca-
fungine reduces symptoms of upper respiratory tract infections demic Press, 1999, pp. 487–501.
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