International SportMed Journal, 2000, Volume 1, Issue 3
© 2000 Human Kinetics Publishers, Inc.
Virus Infections and Chronic Fatigue
in Athletes: Is There a Link?
CR Madeley
Viruses are frequently blamed for a fall (often sudden) in athletic performance. This does not only affect
the élite, but athletes at all levels. Although commonsense suggests that in some cases a virus that spreads
systemically could be involved, there is a serious lack of any corroborative hard evidence. Because viral
infections are very common and mostly trivial, only a well-constructed prospective study can establish
beyond doubt the role of viruses in longer-term sequelae. This review attempts to explain why this is so,
and discusses the major practical problems that will be encountered by anyone trying to collect such hard
data. The study will have to be comprehensive, is likely to encounter ethical questions, may not produce
any positive results, and will be expensive.
Key Words: viruses, athletes, chronic fatigue, athletic performance
Key Points:
• Viruses are often blamed, on little or no evidence, for a loss in athletic performance. Viruses, however,
can produce a systemic malaise, which makes the sufferer unwilling, or unable, to do his/her best.
• Some viruses may be more likely causes than others. Coxsackie B viruses are known to infect muscle, but
there are as yet no good data that implicate them unequivocally in long-term fatigue.
• Confirming the role of particular viruses in longer-term fatigue requires a well-planned and
comprehensive prospective study to identify which viruses are involved. Such a study will require highquality virology, bacteriology, immunology, and hematology, as well as thorough and objective fitness
assessments by a sports physiologist.
• The setting up of such a study will encounter ethical as well as cost problems and, due to the
unpredictability of viruses and other microorganisms, may fail to produce any positive results. In their
absence, the case is “not proven.”
Introduction
The simple, and intuitive, answer to the question Is there a link between virus infections and chronic fatigue in
athletes is “Yes . . . probably,” but may be very difficult to prove either way. There is a logical train of thought that
viruses cause infections which result in disease and discomfort. These make the sufferer feel awful and disinclined
to do physical things. If this happens to a trained athlete, his/her performance will fall off, and it is a short step to
blame a significant and extended fall-off in athletic performance on “a virus.” However, this logic is flawed, because
a loss of condition/competitiveness may have a variety of, and even multiple, causes.
Crucially, some of these causes will not have a demonstrable physical basis. Those training to a peak of fitness, by
definition, are pushing themselves to the limit where the differences between one athlete and another are very small.
Even a temporary drop in confidence may make the difference between winning and coming second. In these
circumstances, having a scapegoat such as a virus may be a powerful need, especially if sponsorship is involved.
This scenario is not confined to top-level athletes. Others playing, for example, club-level squash and thus not so
highly stressed physically have also found their performance and stamina suddenly diminished and remaining at a
low level for a long period. They, too, wonder if a “virus” was to blame. If it persists, this phenomenon has been
well recorded as “chronic fatigue syndrome” or “Myalgic Encephalomyelitis.” However, there are no unequivocal
tests to confirm the diagnosis or a viral involvement, and the condition has become a battleground between
physicians, psychiatrists, and patients (1–3). Some medium-term consequences of viral infections, such as postinfluenza depression, are well established, but a trigger or a continuing role for viruses in many of the longer-term
alleged sequelae of virus infections has not been scientifically proven to the satisfaction of virologists. Although
there have been reports of the persistence of enteroviral proteins (4, 5), these are not completely convincing and
have yet to be confirmed.
Proving that viruses do play a demonstrable role in chronic fatigue requires a comprehensive prospective study,
which will be expensive to undertake and cannot guarantee to produce the necessary proof. Some of the reasons why
the role of viruses in chronic fatigue will be difficult to prove lie with the nature of viruses, the way they infect the
body, the recovery process and personal attitudes to sporting prowess. If viruses are to be blamed for these often
long-term effects, the evidence must be convincing.
Viruses and Disease
Viruses are very common causes of (mostly minor) diseases. It has been estimated that the average person has about
three virus infections a year, more in childhood, and fewer as one gets older (6). Specimens for a confirmatory
laboratory diagnosis are taken from only a small proportion and mostly only from those patients who are admitted to
hospital. For the great majority, the illness is dismissed as “just a virus,” the sufferer told to wait, in bed or out of it,
with or without general non-specific treatment, and all will be well. In truth, this is often good practical advice and
considerable extra demands on health service resources would have to be made to take further the investigation and
management of what are usually self-limiting conditions.
Viruses are obligate intracellular parasites that must enter some of the cells of the body to replicate their kind, which
is the virus’ objective in invading a new host. The normal internal mechanisms of these cells are then diverted into
making new virions (virus particles). This distortion of the internal milieu usually means that the cell will break up
and die as the new virus particles are released. Virus replication is highly productive with the progeny from one cell
running into thousands, but, overall, the invasion and the resultant damage are rarely fatal to the patient as a whole.
This is because viruses are often very selective in the cells they infect, and even in severe infections, the proportion
of the total body cells involved is very small. Nevertheless, if the cells involved are vital to its survival, this may still
cause the host’s death. Rabies, human immunodeficiency virus (HIV), hepatitis B, polio, and smallpox may all be
fatal for this reason, although only rabies appears to be inevitably so. The final outcome of a virus infection will
depend on the particular virus, how and where it multiplies, how soon it runs out of susceptible cells, and the speed
and level of the mobilization of the body’s humoral and cellular defenses.
This review is not concerned with these severe viruses. Few athletes at any standard of performance will be able to
continue to do their best while infected by them, with the possible exception of those with HIV, before AIDS
develops. Much more relevant are the common viruses widely prevalent throughout the world and normally causing
apparently trivial illness but which, in some cases, may lead to persisting damage that reduces an athlete’s
performance levels.
A Virus Infection
To plan a prospective study on the effects of viruses on performance, it is essential to understand the processes and
events during an infection, what must be done to confirm that it has happened, and which virus was implicated. The
profile of a typical virus infection is shown in Figure 1. As with other generalizations, this is a simplification but
illustrates the general principles of what happens in the majority of cases. The figures along the X-axis are events,
not a scale of time. At point 1, the host is exposed to the virus, and there follows an incubation period between
points 1 and 3. Its length varies from a few hours to weeks or even months and is characteristic of each virus. It is
shorter with respiratory viruses, where the target organ is directly accessible to the incoming virus, and longer where
the virus has to migrate from the point of entry to the target organ. That, too, is an over-simplification of very
complex processes but illustrates the concept. At point 2, shortly before point 3 when the symptoms develop, virus
replication will usually raise the amount of virus to detectable levels in the infected organs and often those affected
as well. (This is not necessarily the same thing, as is discussed under “Virus Diagnosis” below.) Virus replication
rapidly reaches a peak, which may occur when the symptoms and signs of disease also reach a peak, and declines
thereafter. In many cases, the virus is no longer detectable after point 4, about 5 days after the patient first feels ill.
As in influenza where many of the symptoms are due to damage to the tissues as toxic substances are released when
the cells die, the peak of discomfort may post-date the peak of virus replication.
The disappearance of a
virus will be closely
related to the start of the
humoral immune
response, initially with
IgM antibody (at point 5),
followed closely by IgG
(at point 6). IgM is
detectable for a relatively
short time (1 month to 1
year, depending on the
sensitivity of the test
used) becoming
undetectable at point 7.
IgG, on the other hand,
Figure 1 — Schematic outline of a typical virus infection. (Reproduced, with
may then persist for the
permission, from Halonen and Madeley [10])
rest of the patient’s life,
though being able to demonstrate its presence depends on which virus is concerned, the test used to detect the
antibody, and its sensitivity. The initial high level may decline from an undefined point 8, but it is likely to be at
least a year after the original infection.
At the same time, secretory IgA antibody can be found on mucosal surfaces and cell-mediated immunity (through
virus-specific T lymphocytes) develops. Routine laboratory tests for specific IgM and IgG antibodies are widely
available, but those for specific IgA and cell-mediated immunity are more tools for research. The importance of this
will be discussed later.
Virus Diagnosis
These are the procedures used to show that a particular virus has been the cause of the illness or malaise. In the
early, acute phase (the time between points 2 and 5 in Figure 1), this involves identifying the virus itself or parts of
it. After the disappearance of the virus, it involves looking for evidence for an immune response. Table 1 lists the
components of a virus that may be detected at the acute stage and the methods that can be used to find them. Finding
each component does not have the same significance, as shown in Table 2, and all tests depend on collecting a
satisfactory specimen from the patient. Ideally, the specimen should be taken from the affected organ, but this may
not always be possible or ethical. More than one organ may be infected, and it may be much easier to collect
specimens from another site. Brain, central nervous system tissue, and muscle are not accessible without invasive
techniques, and using them will not be justifiable in every case. Collecting specimens of urine, feces, or even throat
swabs will be easier to justify, but is not always direct. For example, coxsackie B viruses may cause a very painful
infection of the intercostal muscles (Bornholm disease), during which they can be readily isolated from feces.
However, they can also be isolated from feces without an associated myalgia. Yet isolation alone does not prove
muscle involvement unless a muscle biopsy is performed.
Recovering the whole infective virus or finding bits of virus implies virus production in progress when the specimen
was taken. With some exceptions, which will be discussed later, the appearance of any of the products of the
Table 1 Detectable Components of a Virus
• Whole infective virus
• Virus genomic nucleic acid(s): DNA or RNA
• Complementary genomic DNA (cDNA): DNA copy of an RNA genome
• Viral messenger RNA (mRNA): virus-specific messenger RNA
• Viral structural proteins: may include glyco- or lipo-proteins
• Viral non-structural proteins
• Viral enzymes: nucleases, neuraminidases, etc.
Table 2 Significance of Finding Components of a Virus
Component
Significance
Whole virus
Production/Persistence of infective virus
Viral genomic nucleic acid (high number of copies)
Active virus replication
Viral genomic nucleic acid (low number of copies)
Virus persistence/low level replication
Viral messenger RNA
Virus production
Viral proteins
Usually virus production
Viral enzymes
Virus activity
immune response implies that the acute infection is now past. From this point onwards, the evidence becomes
increasingly indirect and less sharply defined in time. Given that some virus infections cause little illness, indirect
evidence obtained later will become progressively less convincing as a reason for a drop in performance. Put
succinctly, only direct evidence at the crucial time links a virus with an effect on the body; retrospective “evidence”
is not strong enough to convict. This means that the traditional “virus titer(s)” are unequivocally useless for proving
viruses to be the cause of chronic fatigue. Although they show that something happened in the past, there is no
indication of exactly when, nor how severe or extensive it was.
Figure 1 does not show, however, the only outcome of an acute virus infection. Some viruses (e.g., herpes viruses,
wart viruses, and HIV) can persist. The herpes viruses, which include herpes simplex types 1 and 2, the viruses of
chickenpox and shingles, cytomegalovirus, Epstein Barr virus, and the later human herpes viruses (types 6, 7, and
8), always persist after the initial infection. Once acquired, they remain inside the body indefinitely and may become
active again when and if the conditions are right.
Usually this reappearance follows a decline, with
time or from immunosuppressive treatment, of
the body’s immunity. Similarly, wart viruses
may also persist and it is thought that both it and
herpes viruses do so by forming their DNA into
circles that are less easily degradable by the
body’s nucleases. HIV, on the other hand,
persists by forming a complementary DNA copy
of the virus’ genomic RNA, which is then
integrated into the genome of the host cell, like
adding another truck into a goods train.
In the case of herpes viruses and the wart virus,
the virus becomes relatively inactive with fewer,
or even no, complete particles being produced.
Some wart viral antigens (proteins) can
transform host cells and make them proliferate
into the physical lesions that we recognizes as
warts, but there is no evidence that these proteins
exert a widespread effect on all the body’s cells.
Two of these viruses have DNA genomes and the
third (HIV) can copy its RNA into DNA using
the enzyme reverse transcriptase (RT) that it
carries with it for the purpose. Figure 2 indicates
the general distribution of DNA and RNA in
cells within the body. The main function of DNA
is to act as a repository of genetic information,
and hence there are mechanisms inside cells to
preserve it. RNA, on the other hand, is a
workhorse, transferring snippets of genetic
information to the ribosomes for translation into
protein. There is no obvious need for this RNA to
be preserved beyond its immediate function, and
Figure 2 — Diagrammatic distribution of the
distribution and roles of DNA and RNA in a typical
mammalian (or human) cell.
good reasons for degrading it as soon as it is no longer needed. Not surprisingly, DNA-containing viruses find it
easier to persist inside cells than RNA-containing ones, and a convincing mechanism by which viral RNA could
persist in an otherwise normal cell has yet to be proposed. Since most of the viruses that have been suggested as
causes of chronic fatigue contain RNA, this immediately poses a practical difficulty without, as yet, a convincing
theory how the virus might surmount it.
Despite these theoretical obstacles, demonstrating that a virus was active anywhere in the body at the crucial time
when performance had declined or just before would give investigators something definite to pursue. At present, the
whole basis is theoretical and a role can be worked out once a candidate culprit has been identified. There are a vast
number of viruses that are known to infect man (probably well over 1,000, if you include distinct serotypes; 7), plus
an unknown number that may still await discovery. There is no a priori reason for excluding any of them, although
it is the RNA-containing enteroviruses that have been most convincingly shown to cause muscle damage. A welldesigned prospective study might both narrow the field and provide the hard starting data on which to develop
further studies. It seems unlikely that one study will be able to answer all the questions.
The Prospective Study
This has been outlined in two previous papers (8, 9), and no further details will be provided here. The main steps are
straightforward:
1. recruit a group of athletes training for a specific event,
2. monitor their developing fitness,
3. identify any infections (especially viral ones) as they occur,
4. document any effects these have on their performance, at the time and subsequently.
Translating this into a scientifically valid project, however, turns out to be less simple as the various parameters are
examined.
1. The Study Group
The most suitable subjects for the study will be track and field athletes. It is easy to measure their performances
objectively, their sport is individual, they train for events on specific dates with a crescendo in their training, and
results do not depend directly on a contribution from others.
As with any other study, the numbers are important. The greater the number of participants, the more statistically
valid the conclusions. However, this has to be moderated by:
• availability (they should train together as a group),
• the logistics of monitoring performance regularly,
• the logistics of collecting and processing weekly specimens,
• the willingness of individuals to participate when they know what will be expected of them,
• costs (of materials and staff, which will escalate rapidly as numbers increase).
Against this, there is a long list of candidate viruses that cause significant loss of “form” (to use a blanket term to
cover all measurable aspects of the effects of a virus on performance), and there may not be a single cause. If several
viruses appear to be involved but each infects only one member of the group, it will be impossible to draw any
quantitative conclusion. This is a theoretical objection, and this author’s belief is that only a small number of viruses
would be involved.
2. Athletic Progress
This would have to be assessed at least weekly and would probably be part of their training routine. However, all
suitable parameters based on stopwatch times/heights/distances achieved would have to be recorded. This could be
more complex with runners, for example, who might concentrate on speed at one period and distance at another.
Weight-training might also yield figures for comparison, as well as other machine-based assessments. A plan to
record statistics that could be compared on a weekly basis would have to be worked out with the athlete and the
coach.
Table 3 The Prospective Study—Weekly Specimens to Be Taken From Each Subject
For virology:
1. Nose and throat swabs in Virus Transport Medium1
2. Stool sample: about 5g1
3. Serum sample: 5ml clotted blood - for antibody tests2
For bacteriology:
1. Nose and throat swabs in Bacterial Transport Medium
2. Stool sample: about 5g1
3. Serum sample: 5ml clotted blood - for antibody tests2
For immunology:
1. Heparinised blood: 50ml2 - for assessments of:
a. Lymphocyte numbers, identity & function (by culture)
b. Measurement of some lymphokine concentrations
For hematology:
1. Citrate blood: 2ml for hemoglobin level and full blood count2
Fitness assessments
In addition to the above, the subjects will be assessed weekly and objectively by a sports
physiologist on fitness machinery appropriate to their sport, and recorded fully.
Note. 1Quantities taken must be enough to allow (further) re-assessments later. 2Wherever
possible, blood samples for all purposes should be taken at one venepuncture, and the quantities
kept to a minimum.
3. The Specimens
Weekly specimens would have to be taken to monitor hematological, immunological, bacterial and virological
parameters. These are listed in Table 3. Although any infection is likely to be overt at the acute stage, this may not
be true in all cases. Thus, it would be necessary to have taken specimens from all the members of the study group to
show the level of infection by the virus and the affect on each individual, if any. In case of a clinical infection,
additional specimens would be needed to document the duration and severity of the episode.
There are at least (!) two serious obstacles to collecting the necessary specimens, even if it is assumed that the
subjects are sufficiently motivated to donate them in the first place as a contribution to science. First, about 50 ml of
blood is required weekly to cover all the necessary regular tests. Most will be for the tests of immunological cell
function (transformation assays), but the T-cells are an essential component of the immune response that lies at the
core of long-term control of virus and virus-infected cells. Taking that amount of blood weekly can lead to a drop in
hemoglobin levels, and this could affect performance. Microtechniques may help here but are not presently
available.
The second obstacle concerns the ethics of taking these specimens from healthy individuals, and some Ethics
Committees might not agree to allow it. If absolute proof of virus involvement were required, possibly as a second
phase in the study, muscle biopsies would have to be conducted, which poses even greater procedural difficulties.
4. Staffing
Except for a small number of professional athletes, whose interest in this type of study may be minimal, most
potential subjects have daytime jobs and train in the evening. Collecting and processing the specimens, some of
which are perishable, will require the staff to work on this project outside normal working hours, adding to
recruitment problems and overall costs. For the sake of consistency, there should be a single coordinator to oversee
the collection of data and specimens, supervise testing, and collate the records. It is too complex to be done on a
part-time basis.
5. Laboratory Back-Up
The study will require routine access to laboratory facilities in virology, bacteriology, viral immunology, and
hematology capable of the range of techniques listed in Table 4. These are not widely available in one place and
likely to be less so in the future as assays become more mechanized.
Table 4 The Prospective Study—Techniques Necessary in the Medical Support Laboratories Involved1
Virology:
1. Cell culture, using primary, semi-continuous and continuous cell types.
2. Rapid methods2 of diagnosis for: a. Respiratory viruses; b. Stool viruses
3. A wide range of serological tests, for both IgM and IgG classes of antibody, where available
4. Viral nucleic acid amplification techniques3
5. Some viral enzyme assays4
6. Viral identification and confirmation techniques5
7. Access to comprehensive reference facilities
Bacteriology:
1. Aerobic and anaerobic culture
2. Bacterial identification and sensitivity techniques
3. A wide range of serological tests, as before
4. Tests for toxin production6
Immunology:
1. Lymphocyte and differential counts
2. Lymphocyte function assays7
3. Lymphokine identification and quantitation
Note. 1These have to be available locally. They cannot be improvised reliably at short notice. 2Such as
immunofluorescence or enzyme immuno-assays (respiratory viruses), electron microscopy (stool viruses). 3Such as
: PCR, LCR or NASBA. 4Virus-specific nucleases or neuraminidases. 5To a type-specific level. 6May need access to
an experimental animal house. 7Such as virus-specific transformation assays. For practical reasons, these may have
to be part of a second phase.
6. Costs
A rough estimate of the costs in 1997 gave a total of £150,000stg (equivalent to about 225,000 Euros or US$).
Grant-providers may be reluctant to provide such a vast sum of money for a project that cannot guarantee to provide
any positive results. This author and colleagues were unable to identify any sports-related body in the UK able to
consider that level of grant.
Conclusions
The purpose in writing this review was not to discourage anyone from attempting this type of study but to highlight
problems that would have to be faced. As indicated, the major one identified is funding, particularly because of the
difficulty of yielding hard data. Nevertheless, the implications of finding a cause or causes for chronic fatigue are
important for many more than just those who aspire to be serious athletes. It would be very difficult to set up such a
study to include members of the general population. It requires the active cooperation of the subjects, who must be
willing to commit to a measured program of training, where any fall-off in capacity can be documented, as well as
providing the necessary specimens. Thus, it demands a high level of commitment that might be difficult to find
elsewhere.
There is a further and presently unquantifiable factor in this equation, namely the athlete’s own mental attitude. This
is extremely difficult to measure, especially if the subject is aware of the purpose of the study and involved in it.
His/her focused determination to win (or not to lose) can be the deciding factor in a competition. To place a
numerical value on this and then to attempt to measure a decline after a virus infection shows how soft such data can
be.
Given this background, it is perhaps not surprising that there is no straight answer to the question posed in the title
of this review. Viruses will continue to be blamed, without good evidence, for a sudden and/or prolonged loss of
form or extended fatigue. A temporal link between physical symptoms and a documented infection could be made
with the study outlined above. It would identify, or fail to identify, a candidate virus or viruses for a second phase
study with or without muscle biopsies. Presently, there are many strongly held opinions on the role of viruses but
little hard data. Should we try to answer some of these questions properly?
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8. Madeley CR. Viruses and athletes. Brit J Sports Med 1998;32:281-286.
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Acknowledgements
The author is very grateful to Dr Ron Scott, enthusiastic amateur footballer and Virologist with a strong interest in
viral immunology at the University of Newcastle, and Dr Phil Hayes, Lecturer in the Department of Physical
Education and athletics trainer of the Department of Physical Education, University of Northumbria, both in
Newcastle upon Tyne, U.K. He also acknowledges many others, who were bothered with questions about funding,
for their patience in putting these ideas together.