Sports Med 2006; 36 (1): 39-64

REVIEW ARTICLE 0112-1642/06/0001-0039/$39.95/0

 2006 Adis Data Information BV. All rights reserved.

The Roles of Exercise-Induced

Immune System Disturbances in the
Pathology of Heat Stroke
The Dual Pathway Model of Heat Stroke
Chin Leong Lim1,2 and Laurel T. Mackinnon1
1 School of Human Movement Studies, University of Queensland, Brisbane,
Queensland, Australia
2 Military Physiology Laboratory, Defence Medical and Environmental Research Institute, DSO
National Laboratories, Singapore

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
1. The Definition of Heat Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
2. The Endotoxaemia Model of Heat Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3. The Role of High Core Temperature in Heat Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.1 Interpretation of Core Temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.2 Variation in Core Temperature Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
3.3 Critical Core Temperature as a Protection Against Heat Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
4. Gastrointestinal (GI) Disturbances During Intense Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
4.1 Effects of Long-Distance Running and Hyperthermia on the Gut . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
4.2 GI Disturbances in Long-Distance Runners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
5. Endotoxaemia: the Primary Pathway of Heat Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
5.1 Lipopolysaccharide Binding and Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
6. Hyperthermia: the Secondary Pathway of Heat Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
7. The Role of the Immune System in Heat Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
7.1 Acute Immune Response to Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
7.2 Chronic Immune Response to Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
7.3 Opportunistic Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
8. The Role of Pro-Inflammatory Cytokines in Heat Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
8.1 Cytokine Response During Heat Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
8.2 Exercise-Induced Cytokine Release and the Mechanism of Heat Stroke . . . . . . . . . . . . . . . . . . . . 55
9. T-Helper Cell 1 and 2 (Th1/Th2) Balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
9.1 Possible Roles of Th1 and Th2 Immunity in the Mechanism of Heat Stroke . . . . . . . . . . . . . . . . . . . . 55
10. Immune Disturbance and Heat Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
11. The Dual Pathway Model of Heat Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
12. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Abstract Heat stroke is a life-threatening condition that can be fatal if not appropriately
managed. Although heat stroke has been recognised as a medical condition for
centuries, a universally accepted definition of heat stroke is lacking and the
pathology of heat stroke is not fully understood. Information derived from autopsy
reports and the clinical presentation of patients with heat stroke indicates that
hyperthermia, septicaemia, central nervous system impairment and cardiovascular
failure play important roles in the pathology of heat stroke. The current models of
40 Lim & Mackinnon

heat stroke advocate that heat stroke is triggered by hyperthermia but is driven by
endotoxaemia. Endotoxaemia triggers the systemic inflammatory response, which
can lead to systemic coagulation and haemorrhage, necrosis, cell death and
multi-organ failure. However, the current heat stroke models cannot fully explain
the discrepancies in high core temperature (Tc) as a trigger of heat stroke within
and between individuals. Research on the concept of critical Tc as a limitation to
endurance exercise implies that a high Tc may function as a signal to trigger the
protective mechanisms against heat stroke. Athletes undergoing a period of
intense training are subjected to a variety of immune and gastrointestinal (GI)
disturbances. The immune disturbances include the suppression of immune cells
and their functions, suppression of cell-mediated immunity, translocation of
lipopolysaccharide (LPS), suppression of anti-LPS antibodies, increased macro-
phage activity due to muscle tissue damage, and increased concentration of
circulating inflammatory and pyrogenic cytokines. Common symptoms of
exercise-induced GI disturbances include diarrhoea, vomiting, gastrointestinal
bleeding, and cramps, which may increase gut-related LPS translocation.
This article discusses the current evidence that supports the argument that these
exercise-induced immune and GI disturbances may contribute to the development
of endotoxaemia and heat stroke. When endotoxaemia can be tolerated or prevent-
ed, continuing exercise and heat exposure will elevate Tc to a higher level
(>42ºC), where heat stroke may occur through the direct thermal effects of heat on
organ tissues and cells. We also discuss the evidence suggesting that heat stroke
may occur through endotoxaemia (heat sepsis), the primary pathway of heat
stroke, or hyperthermia, the secondary pathway of heat stroke. The existence of
these two pathways of heat stroke and the contribution of exercise-induced
immune and GI disturbances in the primary pathway of heat stroke are illustrated
in the dual pathway model of heat stroke. This model of heat stroke suggests that
prolonged intense exercise suppresses anti-LPS mechanisms, and promotes
inflammatory and pyrogenic activities in the pathway of heat stroke.

Heat stroke is a fatal condition that can be life
threatening if not managed appropriately. Although
heat stroke is one of the oldest known medical
conditions,[1] the pathophysiology of heat stroke is
not fully understood.[2] Except for heat stress, the
other clinical features of heat stroke are similar to
those observed in patients with sepsis,[3,4] suggesting
that the immune system is involved in the develop-
ment of heat stroke. Recent models of heat stroke
suggest that it is triggered by systemic inflammation
in response to endotoxaemia, when endotoxins, also
known as lipopolysaccharides (LPS), migrate from
the gut into the sterile environment of the circula-
tion.[3,5-7] This triggers the systemic inflammatory
response (SIR) and leads to disseminated intravas-
cular coagulation (DIC), necrosis of organ tissues,
and multi-organ failure (MOF), which are common-
ly observed in patients with heat stroke.[2,3,5-8] The
failure of the immune system to remove LPS from
the circulation, and the resulting activation of the
immune cells (monocytes and neutrophils) and
cytokines (tumour necrosis factor-α [TNFα] and
interleukin [IL]-1β) that promote inflammation, are
centrally involved in the development of these
clinical features of heat stroke.[7-11]
It has been suggested that athletes performing
strenuous training might be at a higher risk of infec-
tion because of transient and possibly prolonged
immune suppression.[12-18] It has also been proposed
that insufficient recovery between successive exer-
cise bouts over a prolonged period of time may
cause chronic suppression of the immune sys-
tem,[19,20] possibly increasing the risk of illness. Pro-
longed endurance running causes disturbances to the
gastrointestinal (GI) system, with symptoms such as
cramps, GI bleeding, diarrhoea and vomiting.[21-27]

 2006 Adis Data Information BV. All rights reserved. Sports Med 2006; 36 (1)
Intense Training, Immune Response and Heat Stroke
Athletes may show symptoms of endotoxaemia[28,29]
(e.g. nausea, vomiting and diarrhoea) and suppres-
sion of anti-LPS antibodies[30] after an endurance
event, such as a triathlon or ultra-marathon (89km).
The combination of exercise-induced disturbance of
the immune system, GI symptomatology, and en-
dotoxaemia are consistent with the endotoxin-relat-
ed mechanisms of heat stroke advocated by the
current heat stroke models.[3,5,7]
LPS is an endotoxin that resides in the cell wall
of Gram-negative bacteria, which are harmless to
the body as long as they remain within the gut
space.[4,24] The gut normally blocks the movement of
bacteria into the circulation, but strenuous exercise
and heat stress increase the permeability of the
paracellular epithelial tight junction, resulting in
LPS translocation from the gut into the portal circu-
lation.[3,4,24,31,32] The immune system scavenges and
clears LPS from the circulation, up to a point,
through the reticuloendothelial system (RES) of the
liver, high-density lipoproteins (HDL), and an-
ti-LPS antibodies.[10,11] Immune suppression during
prolonged strenuous exercise may compromise the
scavenging and removal of circulating LPS by de-
creasing the concentration of circulating anti-LPS
antibodies.[28-30] Endotoxaemia develops when the
rate of LPS clearance cannot keep pace with the rate
of LPS translocation, causing LPS to leak into the
central circulation. Heat and exercise-induced en-
dotoxaemia may trigger the symptoms of heat
stroke.[3,24]
The occurrence of heat stroke in soldiers also
coincides with periods of intense training and recent
bouts of infection,[33-35] suggesting that heat toler-
ance is compromised by a weakened immune sys-
tem. The common features of heat stroke, sepsis,
immune suppression, GI disturbances and endotox-
aemia after prolonged intense exercise suggest the
existence of a common pathway between a compro-
mised immune system and heat stroke. This review
discusses the literature on heat stroke, the immune
response to exercise, and endotoxaemia during exer-
cise and heat stress, and provides evidence to sup-
port the argument that exercise-induced changes in
immune function are causally related to heat stroke.
We also propose a dual pathway model of heat
stroke, which integrates the exercise-induced im-
 2006 Adis Data Information BV. All rights reserved.
41
mune disturbances with the endotoxaemia model of
heat stroke.[3,5,7]
1. The Definition of Heat Stroke
Although there is general agreement on the key
features of heat stroke, a universal definition of heat
stroke has yet to be developed.[36] The characterisa-
tion of heat stroke (table I) comes from reports on
the clinical and forensic descriptions of heat stroke
victims.[34,37-39] Anderson et al.[40] defined heat
stroke as a state when core temperature (Tc) rises
above 40ºC, which is accompanied by hot, dry skin
and abnormalities of the CNS. Others defined heat
stroke as a ‘form of hyperthermia, associated with a
systemic inflammatory response leading to a syn-
drome of multi-organ dysfunction in which en-
cephalopathy dominates’.[5] Using these definitions,
heat stroke can be characterised as a systemic condi-
tion that includes Tc >40ºC, an inflammatory re-
sponse, CNS dysfunction (e.g. coma, delirium, con-
vulsion), DIC and MOF. Hot, dry skin and cardio-
vascular deterioration may be observed at times.
These features merely characterise the observations
of heat stroke patients (table I) and do not represent
a universal definition of heat stroke.
2. The Endotoxaemia Model of
Heat Stroke
Heat stroke has been attributed to the effects of
extreme internal heat load on cardiovascular and
hypothalamic functions[34,37,44,50-55] and direct ther-
mal injury on organ tissues.[37,56-59] However, these
factors by themselves cannot explain fully the obser-
vation of systemic coagulation, massive haemor-
rhages, and other sepsis-like clinical symptoms in
heat stroke patients. The model for heat stroke has
evolved to the current view that heat stroke is driven
by septicaemia arising from the translocation of
endotoxin from the gut into the circulation under
heat stress conditions.
The endotoxaemia model of heat stroke was
based on observations that heat stroke patients share
a similar clinical presentation as patients with sep-
sis,[8,34,38,60] and that the methods to treat sepsis
increase heat tolerance and survival in animals ex-
periencing heat stroke.[61-64] Moseley and Gisolfi[3]
hypothesised that under heat stress, the permeability
Sports Med 2006; 36 (1)
 2006 Adis Data Information BV. All rights reserved.

42
Table I. Definition and characterisation of heat stroke from 1967 to 2002

Original publication Tc (°C) CNS dysfunction Organ DIC Hot and Cardiovascular Others
(year) failure dry skin changes

Shibolet et al.[34] (1967) Hyperthermia Yes Yes Systemic

disorder

Clowes and O’Donnel[41] (1974) >41 Yes Yes Sweat glands

still active

Shvartz et al.[42] (1977) Elevated Yes Yes

Shapiro et al.[43] (1979) Elevated Yes Yes Yes

Costrini et al.[44] (1979) >40 Coma, delirium Yes Hypotension, Hyperventilation

tachycardia

Anderson et al.[40] (1983) Hyperthermia Coma, delirium, convulsion

Bouchama et al.[8] (1993) Yes Yes

Knochel and Reed[45] (1994) >40 Coma, delirium, convulsion Yes

CDC (US)[46] (1995) ≥40.6a

Barrow and Clark[47] (1998) ≥40.5 Yes

Yaqub and Al Deeb[48] (1998) ≥40 Coma Yes Rhabdomyolysis

Samarasinghe[49] (2001) >40 Delirium, coma, agitation, Yes

Bouchama and Knochel[5] (2002) Hyperthermia Encephalopathy Yes Inflammatory

Sports Med 2006; 36 (1)

response

Lim & Mackinnon

a This is the definition for heat-related deaths, diagnosed together with other circumstantial evidences.

CDC = Center for Disease Control; DIC = disseminated intravascular coagulation; Tc = core temperature.
Intense Training, Immune Response and Heat Stroke
of the gut epithelium may be compromised by cuta-
neous vasodilation and splanchnic vasoconstriction,
due to the effect of high temperature, oxidant injury,
ischaemia, reperfusion, and recruitment of inflam-
matory cells. Increased gut permeability allows LPS
residing in the gut flora to migrate into the portal
circulation. This process overwhelms the liver with
LPS, which leaks into the central circulation (en-
dotoxaemia) and induces the SIR, resulting in necro-
sis, DIC, MOF, and other symptoms commonly
observed in heat stroke patients.
The endotoxaemia model advocates that heat
stoke is triggered by hyperthermia, but its mecha-
nisms are driven by septicaemia and systemic in-
flammation. Direct evidence supports the link be-
tween an increase in gut permeability with intense
exercise and heat stress,[31,65,66] and LPS transloca-
tion and endotoxaemia,[62,63,67] which trigger the de-
velopment of heat stroke in humans [34,38,60] and
animals.[62,64] Once heat stroke is triggered, the pro-
gression of clinical symptoms in heat stroke patients
is positively associated with inflammatory cytokine
activity, but not with Tc.[60] Endotoxaemia is also a
consistent clinical feature in heat stroke pa-
tients[34,38,60,68] and animals.[61-63,67,69]
Other researchers have extended the endotox-
aemia pathway to explain further the pathology of
heat stroke. For example, Hales and Sakurada[7]
expanded the endotoxaemia model of heat stroke to
include the role of fever in the development of heat
stroke. Bouchama and Knochel[5] attributed thermo-
regulatory failure to an overdriven cardiovascular
system that cannot dissipate heat fully, an exagger-
ated acute phase response, and an attenuated heat-
shock response in the endotoxaemia-driven pathway
of heat stroke. This topic has been discussed in
greater details in previous reviews.[3,5,7]
3. The Role of High Core Temperature in
Heat Stroke
Although there is evidence showing a link be-
tween heat stress, LPS translocation, endotoxaemia
and systemic inflammation during heat stroke, the
role of a high Tc remains debatable. The endotox-
aemia model views hyperthermia as a trigger, but
not the driver, of heat stroke.[3,6,8] A high Tc causes
LPS leakage from the gut, which in turn drives the
pathway of heat stroke. If a high Tc does trigger the
 2006 Adis Data Information BV. All rights reserved.
43
onset of heat stroke, then heat stroke would consist-
ently be triggered once Tc rises to a specific level.
However, experimental evidence does not support a
linear relationship for hyperthermia-induced en-
dotoxaemia-driven heat stroke. Heat stroke can oc-
cur in trained and experienced athletes[70-73] and
soldiers[34,38] performing work that had been previ-
ously well tolerated, suggesting that the same level
of exercise and heat stress may not always lead to
heat stroke in a given individual. Moreover, there is
a great deal of overlap of Tc in heat stroke vic-
tims,[74-76] and in healthy and conscious athletes[77-82]
and soldiers[83] who did not develop heat stroke.
This evidence suggests that a high Tc does not
uniformly trigger the mechanisms of heat stroke and
that heat intolerance might be transient and some-
what dependent on other factors.
3.1 Interpretation of Core Temperature
Tc is a measure of the total heat storage within
the body, which is a function of metabolic heat
production and heat exchange with the external en-
vironment through the processes of conduction, con-
vection and radiation, and heat dissipation through
evaporation.[51] The resting Tc of 37ºC is easily
understood and remains relatively constant in nor-
mal healthy individuals.[1] At the other extreme, a Tc
of >40ºC can be considered dangerous because of its
association with tissue damage and mortali-
ty.[6,52,84,85] It is difficult to interpret a Tc ≥40ºC,
because it may occur under varied physiological
states such as strenuous physical exertion (heat
stress),[78,80-82] fever,[7,51] or the pathological
processes associated with heat stroke.[8,86,87] Some
authors have argued that the mechanisms of heat
stroke differ from those of fever.[51] However, the
moderate increase in Tc in heat-stressed sheep in-
duced by the injection of the anti-pyrogenic drug,
indometacin, suggests that heat stroke and fever
share some common pathways.[7,66] Under exercise
and heat stress conditions, the mechanism for deter-
mining the overriding physiological state (fever,
heat stroke, or heat stress) at Tc ≥40ºC is currently
not well understood, making accurate prediction of
heat illness based on Tc unreliable. By itself, Tc is
best used to quantify heat load in the body but is not
a reliable predictor of the onset of heat stroke.
Sports Med 2006; 36 (1)
44
3.2 Variation in Core Temperature Response
Although heat stroke patients typically exhibit Tc
ranging from 40 to 43ºC,[87-89] emergency responses
have been activated for those with Tc as low as
38ºC[75] (measured within 15 minutes of collapse)
and as high as 47ºC.[39] The physiological signifi-
cance of a high Tc is further complicated by reports
of healthy and conscious runners and soldiers with
Tc of 40.6–41.3ºC,[77-83] whereas some heat stroke
victims have died with a Tc of 40ºC.[86,87] In addi-
tion, only 10–20% of heat casualties were observed
to have Tc >42ºC (measured on site); the other heat
casualties exhibited Tc similar to those reported in
healthy runners.[74,75]
The clinical progression of heat stroke dissoci-
ates from Tc once heat stroke has been trig-
gered,[3,8,85] implying that although a high Tc is a
pre-requisite for heat stroke to occur, an elevated
temperature alone does not trigger the onset of heat
stroke. It appears that heat stroke may be triggered
by intermediate mechanisms activated by a high Tc.
A high Tc may provide the necessary condition for
heat stroke to occur by facilitating LPS translocation
and the actual trigger of heatstroke might be influ-
enced by the ability to tolerate LPS. For example,
endotoxaemia was detected at the end of the race in
endurance athletes who displayed symptoms of en-
dotoxaemia but not heat stroke.[28,29] The degree of
endotoxaemia is inversely related to the concentra-
tion of anti-LPS antibodies,[28,29] and the concentra-
tion of anti-LPS antibodies, in turn, is inversely
related to the concentration of TNFα,[30] a pro-
inflammatory cytokine induced by endotoxaemia.
Data from animal experiments suggest that heat
exposure alone may not fully explain the develop-
ment of thermal tolerance.[85] Rats subjected to sub-
lethal intravenous injection of LPS for 5 days had a
significantly higher RES clearance rate and thermo-
tolerance than control animals during a heat stress
test (Tc >42ºC). These were similar in rats treated
with sub-lethal heat exposure (41.4–41.8ºC) for only
3 days, implying that besides heat exposure, thermo-
tolerance can be induced by the stimulation of RES
clearance through other means. Furthermore, be-
cause the RES of the liver is the main clearance site
for circulating LPS, the concurrent increase in the
RES clearance rate and thermo-tolerance suggests
 2006 Adis Data Information BV. All rights reserved.
Lim & Mackinnon
that heat stroke may be triggered by a failure of the
anti-LPS mechanism to curb the increase in circulat-
ing LPS. High Tc is more likely to act as a facilitator
and not a trigger of heat stroke, although this role as
a facilitator and not a trigger of heat stroke is re-
stricted to the Tc levels observed during endotox-
aemia.
Animal studies have shown that preventing or
tolerating endotoxaemia during continued exposure
to heat stress may cause Tc to rise to an extreme
level (>43.5ºC) when heat stroke can occur because
of the direct thermal effects of heat on tissue
cells.[61,62] Blocking LPS activities (e.g. via cortico-
steroid, anti-LPS antibodies and antibiotics) in
monkeys resulted in significantly higher thermo-
tolerance than in control animals at Tc
43.5ºC.[61-63,67] Although all animals died when Tc
was elevated to >43.5ºC, LPS concentration in
monkeys treated with anti-LPS agents were only
slightly elevated above resting level, whereas con-
trol animals had endotoxaemia. This evidence sup-
ports the argument that heat stroke is driven by two
different but connected pathways. The first pathway
of heat stroke is driven by endotoxaemia and the
second pathway is driven by the direct thermal ef-
fect of heat on tissue cells. These two pathways of
heat stroke and the relationship between them are
discussed in detail in sections 5 and 6.
3.3 Critical Core Temperature as a
Protection Against Heat Stroke
A Tc >40ºC also represents a critical level where
fatigue occurs, irrespective of initial Tc or the rate of
heat storage.[90] For example, under heat stress,
trained cyclists achieved volitional fatigue at a uni-
form Tc of 40.1–40.3ºC,[90] which is known as the
‘critical temperature’ (i.e. the Tc where fatigue sets
in). The Tc observed in these exhausted cyclists is
consistent with that documented in military recruits
in the last phase of a 16km march and other military
training activities (unpublished data). In rats, the
critical rectal temperature of 42.2–42.5ºC was ob-
served at the point of fatigue.[91] Variation in envi-
ronmental conditions (33–38ºC) does not alter the
critical brain (40.1–40.2ºC) and intra-abdominal
(39.8–39.9ºC) temperatures at the point of fa-
tigue.[92] These studies support the concept of a
critical body temperature beyond which exercise
Sports Med 2006; 36 (1)
Intense Training, Immune Response and Heat Stroke
performance is inhibited and which may also serve
to prevent over-heating.[93,94]
It is impossible to separate the dual role of a
critical temperature that both inhibits exercise per-
formance and prevents heat stroke because inhibi-
tion of exercise reduces heat production and storage.
The mechanism for the dual role of critical tempera-
ture exists in the hypothalamus.[93-95] The critical Tc
inhibits exercise performance through increased
heart rate and skin blood flow, and decreased cardi-
ac output, stroke volume[90,93] and neural drive.[93,94]
These functions are also influenced by the hypothal-
amus through the hypothalamic-pituitary-adrenal
(HPA) axis mechanisms.[96,97] An important patho-
logical question, is whether the critical temperature
at which exercise is inhibited is equivalent to the
critical temperature for heat stroke. Because the
hypothalamus also regulates body temperature,[51] it
is possible that the critical Tc signals the hypothala-
mus to initiate the inhibition of exercise perform-
ance through the moderation of cardiovascular and
neural functions.[51,93] Thus, although a high level of
heat stress may not play a direct role in triggering
heat stroke, the critical temperature may function as
an important signal for the brain to activate its
protective mechanisms against heat stroke by inhib-
iting exercise performance.[90,93,98] The critical Tc
threshold, therefore, could be the buffer between
tolerable or sub-lethal heat stress and the trigger that
initiates the cascade of events leading to heat stroke.
The breaching of this critical Tc level may set the
conditions required to activate the endotoxaemia-
driven pathway of heat stroke.
4. Gastrointestinal (GI) Disturbances
During Intense Exercise
The GI mucosa separates the body’s sterile inter-
nal environment from the non-sterile environment
of the gut. A plethora of >400 species of bacteria
live in the gut space;[24] LPS is located in the walls of
Gram-negative bacteria.[66] These bacteria are harm-
less when confined to the gut, but can be harmful
when they migrate across the gut epithelial tissue
into the circulation. Although a small amount of
bacteria routinely leaks through the gut epithelium,
the bacteria are efficiently detoxified and cleared by
the liver without affecting the central circulatory
environment.[10,11,24,62,69]
 2006 Adis Data Information BV. All rights reserved.
45
4.1 Effects of Long-Distance Running and
Hyperthermia on the Gut
Despite its critical role as a ‘gatekeeper’ of the
sterile internal environment, the gut does not re-
spond well to prolonged exercise.[7,99] Blood flow to
the intestine is reduced by about 80% during exer-
cise,[100,101] and this reduction is exacerbated by
hyperthermia.[3,66] Reduced blood flow to the gut
may persist for some time after prolonged exercise.
For example, splanchnic blood flow was reduced by
60% for 90 minutes after a 20km run.[102] Splanchnic
partial pressure of oxygen (pO2) and pH declined
significantly and hypoxia-labelled cells (using
{H}misonidazole) in the intestine increased signifi-
cantly during hyperthermia.[103] Gut ischaemia and
hypoxia increases the permeability of the paracellu-
lar tight junctions in the gut epithelium,[3,6,7,65] As a
consequence, larger molecules in the gut space that
would not normally pass through the epithelial tight
junction at rest can be translocated across the gut
membrane into the portal circulation under exposure
to exercise and heat stress.[31,65]
4.2 GI Disturbances in
Long-Distance Runners
Alterations in membrane permeability and is-
chaemia in the gut accompany GI disturbances in
long-distance runners. Symptoms of GI distur-
bances in endurance runners include abdominal
cramps, diarrhoea, vomiting, nausea and bloody
stool.[21-23,25-27,104,105] A survey of 134 runners re-
ported that diarrhoea (47%), bloody stool (16%),
and severe lower abdominal cramps (36%) occurred
frequently after intense running.[26] Eichner[105] re-
ported that 13–42% of marathon runners exper-
ienced GI bleeding in six different marathons.
Others have observed GI bleeding in 8–22% of
marathon runners and 85% of ultra-marathon run-
ners.[25] Along with these GI symptoms, endotox-
aemia has also been documented at the end of ultra-
endurance events.[28-30] Marathon runners who de-
veloped bloody stools were significantly younger
and ran faster times than those with normal
stools.[23] An abrupt increase in training volume is
also associated with GI bleeding.[21] High-intensity
running at 80% maximum oxygen consumption
(V̇O2max) significantly induces greater gut epithelial
Sports Med 2006; 36 (1)
46 Lim & Mackinnon

Endurance exercise and hyperthermia

Direct
thermal effect Gut ischaemia, hypoxia,
with LPS acidosis and excessive jarring
tolerance

Mucosa erosion, GI haemorrhages LPS translocation

LPS tolerance
Endotoxaemia

Diarrhoea, bloody stool,

nausea and abdominal cramps
Systemic
inflammatory response

Massive haemorrhage and death Heat stroke

Fig. 1. Gastrointestinal (GI) response during endurance exercise and heat stress. Endurance exercise and hyperthermia cause erosion of
the mucosa in the GI tract, and promote lipopolysaccharide (LPS) translocation from the gut into the portal circulation. Excessive LPS
translocation can result in endotoxaemia, which eventually leads to heat stroke. Athletes who are tolerant to LPS continue to exercise
intensely, which may cause other forms of GI disturbances (e.g. diarrhoea, bloody stool, nausea, abdominal cramps and haemorrhages)
that can be fatal in extreme cases.

permeability compared with no exercise, and with
running at 40% and 60% V̇O2max.[31]
Bloody diarrhoea in runners has been attributed
to hyperthermia-induced gut ischaemia.[22] This is
consistent with the observation that rats with Tc of
42.5ºC had higher gut permeability than those with
lower Tc and with the histological analysis of gut
tissues that revealed intestinal epithelial damage in
rats heated to Tc >41ºC.[65] Examination of mara-
thon runners 95–180 minutes after the race using GI
endoscopy and a creatinine-labelled macromolecule
biomarker revealed weaknesses of mucosal resis-
tance, reflecting damage to the intercellular junc-
tions, increased intestinal permeability, gastric mu-
cosal erosion, and bleeding in the abdomen and
small intestine.[102] In an extreme case, a 28-year-old
runner bled to death from haemorrhagic gastritis
while jogging.[106] The mechanical jarring of the GI
associated with running, but not with lower-impact
activities, has also been implicated in causing GI
disturbances.[25,27,104,107] Running induces twice the
degree of vibration in the abdominal region com-
pared with cycling.[108]
The evidence presented in this section strongly
suggests that GI disturbances caused by long-dis-
tance running can promote the translocation of LPS
from the gut into the circulation (figure 1). This
observation is consistent with the occurrence of
endotoxaemia[28,29] and heat stroke[74-76] reported
among long-distance runners and triathletes.
5. Endotoxaemia: the Primary Pathway
of Heat Stroke
Endotoxaemia is septicaemia caused by endotox-
ins residing in the cell walls of Gram-negative bac-
teria. Endotoxaemia develops when there is an in-
crease in LPS concentration in the central circula-
tion. Heat stroke patients show symptoms of
endotoxaemia.[34,37,38,87,109] For example, one study
reported plasma LPS level of 8.6 ng/mL in heat
stroke patients,[60] which is much higher than the
lethal concentration of 1 ng/mL.[29] Animal studies
also associate heat stroke with endotoxaemia. For
example, plasma LPS concentration increased by an
average of 4.8-fold (range 2.9- to 7-fold) in animals
subjected to heat stroke.[62,64,67,69,110] The clinical
features of heat stroke are similar to those of sepsis
caused by other conditions. Treatment for sepsis
with anti-LPS antibodies,[62] corticosteroid,[61] non-
absorbable antibiotics,[67] and gastric lavage[64] are
effective in attenuating the symptoms and progres-
sion of heat stroke in animals.

 2006 Adis Data Information BV. All rights reserved. Sports Med 2006; 36 (1)
Intense Training, Immune Response and Heat Stroke
During heat stress, the gut becomes is-
chaemic[66,102,111] and hypoxic,[102,103] altering the
permeability of its epithelial layer and promoting the
translocation of LPS from the gut flora into the
sterile environment of the circulatory sys-
tem.[65,102,110,112-115] Most studies agree that LPS is
first translocated from the gut into the portal veins
before gaining entry into the central circulation via
the liver.[3,24,28,29,65] However, Gathiram et al.[110]
suggested that severe heat stress might cause LPS to
leak into the circulation by other routes (e.g. lym-
phatic vessels).
5.1 Lipopolysaccharide Binding
and Clearance
Endotoxin is degraded in the liver by hepatic
Kupffer cells and other cells (e.g. monocytes neutro-
phils, basophils, eosinophils and mast cells) in the
RES.[10,11,24,85,115-117] The liver has a limited capacity
to neutralise and remove LPS; once this threshold is
reached, LPS spills over into the central circulation
resulting in endotoxaemia.[4,24,29,69] Free (unbound)
circulating LPS becomes inactivated when bound to
HDL in animals and low-density lipoproteins (LDL)
in humans.[10,11,110,118,119] For example, LDL inhibits
in vitro production of monokines induced by LPS;
HDL also inhibits monokine production, but to a
lesser degree.[118] Anti-LPS antibodies of the immu-
noglobulin (Ig)G and IgM subclasses also helps
control the level of circulating LPS.[30] Anti-LPS
antibodies binds to biologically active sites of LPS
and promotes its opsonisation and clearance in the
liver.[11,30,117] The efficacy of anti-LPS antibodies in
preventing endotoxaemia was demonstrated in heat-
stressed monkeys. When Tc of monkeys was elevat-
ed to 43.5ºC, the survival rate was significantly
higher in those treated with anti-LPS antibodies
(100%) than in control animals (16%).[62] Although
all the monkeys died when Tc was elevated to
43.8ºC, those treated with anti-LPS antibodies sur-
vived five times longer than control animals. In both
instances, treatment with anti-LPS antibodies atten-
uated the rise in plasma LPS concentration from pre-
heat exposure levels, whereas control animals ex-
hibited endotoxaemia.
In humans, serum concentrations of anti-LPS
IgG and IgM significantly decrease after strenuous
endurance exercise, and anti-LPS IgG and IgM con-
 2006 Adis Data Information BV. All rights reserved.
47
centrations are inversely correlated with the concen-
tration of plasma endotoxins.[28-30] These relation-
ships reflect the degree of anti-LPS antibody bind-
ing to free LPS[30,63] and the protective roles of anti-
LPS antibodies against endotoxins, which may af-
fect heat tolerance. The concentration of anti-LPS
IgM is inversely correlated with the magnitude of
increase in TNFα after a triathlon race, suggesting
that the response of TNFα to intense exercise is
down-regulated by anti-LPS IgM.[30] This is impor-
tant in preventing heat stroke, since TNFα plays an
orchestrating role in the inflammatory response to
heat-induced endotoxaemia.
Researchers agree that trained athletes have a
higher concentration of circulating anti-LPS antibo-
dies than untrained individuals, which may be due to
frequent exposure to sub-lethal LPS transloca-
tion.[28-30,85] This could explain the higher degree of
heat tolerance among endurance athletes who can
tolerate Tc >40ºC without succumbing to heat
stroke.[80-82] The post-exercise concentration of anti-
LPS antibodies, however, remains lower than pre-
exercise values for 24 hours,[30] suggesting that anti-
LPS capacity may be compromised over an extend-
ed period. Tolerance against heat-induced endotox-
aemia might be further compromised if multiple
bouts of intense exercise are undertaken without
sufficient opportunity for the concentration of anti-
LPS antibodies to be restored. The concentrations of
serum and plasma IgG and IgM are suppressed
during an intense phase of training in endurance
runners, swimmers and various other ath-
letes.[17,120,121] The extended suppression of anti-LPS
antibodies arising from multiple bouts of intense
exercise could partly explain the transient heat intol-
erance and occurrence of heat stroke in trained indi-
viduals
LPS concentration starts to rise in the central
circulation when the anti-LPS mechanisms are una-
ble to cope with the LPS flux from the gut.[7] The
appearance of translocated LPS in the central circu-
lation is a critical step in the development of heat
stroke, and is also considered the critical stage in the
progression from heat stress to the pathological heat
stroke.[7] Heat stroke occurring through endotox-
aemia may be more appropriately labelled as ‘heat
sepsis’ since the pathology reflects that of sepsis and
not of stroke under high heat stress.
Sports Med 2006; 36 (1)
48
6. Hyperthermia: the Secondary
Pathway of Heat Stroke
The evidence presented in section 5 supports the
argument that breaching the critical Tc may trigger
the primary pathway of heatstroke (i.e. endotox-
aemia). Blocking or controlling the primary path-
way of heat stroke by pharmaceutical agents causes
Tc to rise with continuing exposure to heat stress at
an extreme level, at which heat stroke occurs
through the direct effect of heat on the cells of
organs. The blocking of endotoxaemia with cortico-
steroid, non-absorbable antibiotics, and gastric lav-
age protected animals from heat stroke at lower Tc
(<43.5ºC), but not higher Tc (>43.8ºC) with no
significant increase in plasma LPS concentra-
tion.[61,62,64,67,122,123] In these studies, the deleterious
effects of heat stroke appear to arise from the direct
effects of heat on tissue cells[61,62,64,67,122,123] and not
from endotoxaemia. The evidence supports the ar-
gument that heat tolerance can be induced by con-
trolling or blocking endotoxaemia up to a certain Tc;
at extremely high Tc (>43.8ºC). However, heat
stroke may occur via the direct effects of heat (i.e.
the secondary pathway of heat stroke).
In a classic experiment, rat organ tissues were
exposed to temperatures of 40–47ºC in vitro and
tissue damage was noted at temperatures between
43–45ºC.[124] The temperature tolerance limit of
43–45ºC agrees with the temperature range of heat
stroke occurring through the direct effect of heat in
vivo studies.[50,125] It is possible that heat shock
proteins (HSP) protect cells from the effects of heat
stress at temperatures <43ºC, but that HSP lose their
protective functions as Tc rises above 43ºC.[5] If so,
this supports the argument that heat stroke can be
triggered at extremely high temperature by the direct
effects of heat on tissue cells. Heat can denature and
unfold cytoskeletal and cellular proteins, causing
cell death,[126-128] which can also trigger the SIR. The
outcomes of necrosis, DIC and MOF are similar to
those caused by the primary pathway of heat stroke.
7. The Role of the Immune System in
Heat Stroke
Immune cell concentration and function can be
suppressed for up to 72 hours following intense
exercise,[129] when dormant pathogens can gain a
 2006 Adis Data Information BV. All rights reserved.
Lim & Mackinnon
foothold and cause an infection. Cumulative im-
mune suppression through insufficient opportunity
for recovery between each exercise bout may result
in chronic immune suppression[19,20] and increased
risk of infection. Heat sepsis results from the failure
of the anti-LPS mechanisms to curb the increase in
circulating LPS.[10,24] Because prolonged intense ex-
ercise is associated with immune suppression and
heat stroke commonly occurs during periods of in-
tense exercise, it is possible that exercise-induced
immune suppression may contribute to the develop-
ment of endotoxaemia in heat stroke.[3,24,116]
7.1 Acute Immune Response to Exercise
The immune response to a single bout of exercise
has been investigated in exercises such as running
(1–3 hours), rowing (2 hours), interval swimming,
cycling and weight training (table II). Most studies
have documented leukocytosis (+53% to +261%),
monocytosis (+18% to +256%), granulocytosis
(+32% to +396%), neutrophilia (+78% to +260%),
and lymphopaenia (–19% to –60%), which persist
for ≥1 hour after exercise. The lymphopaenia is
accompanied by reduced concentrations of natural
killer (NK) cells (–60% to –80%), B cells (–8% to
–40%), T cells (–14% to –50%), T-suppressor cells
(–40% to –60%), and T-helper cells (–5% to –52%).
These immune changes are transient and resting
values are restored within 6–24 hours.[14,130]
Two immune functions affected by prolonged
exercise are NK cell cytotoxic activity (NKCA) and
the proliferative response of lymphocytes when
challenged with a mitogen in vitro. NKCA de-
creases by 43% to 61% for up to 2 hours after
strenuous exercise.[137,139,142,144,151] NK cells may be
shifted from the circulation into other lymphoid
compartments through the effects of cortisol,[144] or
may enter damaged skeletal muscles as part of the
tissue repair process.[153] Lymphocyte proliferation
in response to phytohaemagglutinin and Con-
canavalin A stimulation declines after strenuous ex-
ercise.[141,142] The decline in lymphocyte function
was attributed to the disproportionate increase in the
ratio of NK to T cells in the circulation.[148,149] NK
cells are involved in scavenging LPS from the blood
and T cells activate B cells, which are essential for
anti-LPS antibody production.[10,11,30] Acute sup-
pression of NKCA and the lymphocyte proliferative
Sports Med 2006; 36 (1)
 2006 Adis Data Information BV. All rights reserved.

Intense Training, Immune Response and Heat Stroke

Table II. Immune response during exercise
Study Study design Immune cell type and Post-exercise ≥1h post-exercise
functions (post – pre) [%] (>1h post – pre) [%]
Low-intensity exercise
Nehlsen-Cannarella et n = 12 women (24–45y) Leu +27 +22 (3h)
al.[131] walking 45 min at 60% Lym +18 –4 (1.5h)
V̇O2max T cell +9 –5 (1.5h)
Lym pr (Con A) +3 +76 (23h)
Lym pr (PHA) +26 –49 (1.5h)
Nieman et al.[132] n = 12 women (24–45y) Leu +27 +22 (3h)
walking 45 min at 60% Lym +18 –4 (1.5h)
V̇O2max Gra +31 +35 (3h)
Mon +29 –16 (1.5h)
Neu +34 +33 (1.5h)
T cell +9 –5 (1.5h)
NK +89 –23 (3h)

High-intensity exercise
Nieman et al.[133] n = 10 marathon runners Leu +153 +178 (1.5h)
performed 3h run on a Lym +19 –19 (1.5h)
treadmill Gra +136 +291 (1.5h)
Mon +67 +79 (1.5h)
T cell +6 –14 (1.5h)
B cell +5 –8 (1.5h)
Gabriel et al.[134] n = 10 cyclists exercised at Gra +20 (EX1); +20 (EX2) +29 (1h) [EX1]; +26 (1h) [EX2]
110% of anaerobic Gra phago activity NC (EX1); NC (EX2) + 9 (1h) [EX1]; +17 (1h) [EX2]
threshold before (EX1) and % Gra phago +2 (EX1); +1 (EX2) NC [EX1]; +2 (1h) [EX2]
7–8d after (EX2) 240km
race
Nieman et al.[135] n = 22 marathon runners Leu +100 +125 (3h)
ran 2.5h run at 70–75% Mon +50 +56 (3h)
V̇O2max Neu +186 +260 (3h)
Lym +9 –41 (1.5h)
T cell –4 –37 (1.5h)
Neu/Lym ratio +147 +503 (1.5h)
Singh et al.[136] n = 14 subjects. 3 × run to Leu +62 (dex); +60 (hyd); +100 (pl) Data for ≥1h post-exercise was not
exhaustion; they consumed Lym +147 (dex); +197 (hyd); +154 (pl) reported
either dex, hyd or pl T cell +94 (dex); +153 (hyd); +86 (pl)
NK +487 (dex); +506 (hyd); +391 (pl)
B cell +76 (dex); +133 (hyd); +80 (pl)
Neu +39 (dex); +35 (hyd); +51 (pl)
Sports Med 2006; 36 (1)

Nieman et al.[137] n = 30 ran 2.5h; n = 17 Lym +15 (CHO); +33 (pl) –24 (1.5h) [CHO]; –26 (3h) [pl]
consumed CHO drink; n = Mon +21 (CHO); +62 (pl) +55 (1.5h) [CHO]; +31 (6h) [pl]
13 consumed pl drink Neu +100 (CHO); +214 (pl) +182 (3h) [CHO]; +257 (3h) [pl]

Continued next page

49
 2006 Adis Data Information BV. All rights reserved.

50
Table II. Contd
Study Study design Immune cell type and Post-exercise ≥1h post-exercise
functions (post – pre) [%] (>1h post – pre) [%]
Gannon et al.[138] n = 6 male competitive Leu +191 +188
cyclists during a 250.5km Gra +356 +396
race Mon +78 +127
Lym +3 –26
T cell –10 –34
NK –22 –38
B cell +58 NC
Miles et al.[139] n = 6 subjects ran 60 min NK +129 –61 (1.5h)
at 80% V̇O2peak Tcell +8 –48 (1.5h)
NKCA +63 –43 (1.5h)
Green et al.[140] n = 12 ran for 60 min at Leu +49 (run); –2 (con) +58 (1.5h) [run]; –3 (1.5) [con]
90% ventilatory threshold; Mon –4 (run); NC (con) –3 (1.5h) [run]; NC [con]
repeated trial design Lym +69 (run); –14 (con) –44 (1h) [run]; –14 (1h) [con]
Neu +65 (run); +7 (con) +170 (1.5h) [run]; +8 (1.5h) [con]
Henson et al.[141] n = 30 ran 2.5h on a Leu +59 (CHO); +127 (pl) +104 (3h) [CHO]; +124 (3h) [pl]
treadmill. n = 17 consumed Mon +21 (CHO); +62 (pl) +66 (3h) [CHO]; +31 (6h) [pl]
CHO drink; n = 13 Lym +5 (CHO); +33 (pl) –24 (1.5h) [CHO]; –26 (3h) [pl]
consumed pl drink B cell +31 (CHO); +29 (pl) +23 (1.5h) [CHO]; +14 (3h) [pl]
NK +26 (CHO); +81 (pl) –63 (1.5h) [CHO]; –58 (3h) [pl]
Neu +100 (CHO); +214 (pl) +182 (3h) [CHO]; +257 (3h) [pl]
Lym pr (Con A) –4 (CHO); NC (pl) –8 (1.5h) [CHO]; –24 (1.5h) [pl]
Lym pr (PHA) –11 (CHO); –35 (pl) –17 (1.5h) [CHO]; –32 (1.5h) [pl]
Lym pr (PWM) +19 (CHO); +34 (pl) +11 (6h) [CHO]; –24 (6h) [pl]
Nieman et al.[142] n = 15 elite female rowers Neu +31 (CHO); +89 (pl) +21 (1.5h) [CHO]; +78 (1.5h) [pl]
consuming CHO or pl on Lym –24 (CHO); –18 (pl) –17 (1.5h) [CHO]; –17 (1.5h) [pl]
separate training sessions T cell –18 (CHO); –16 (pl) –11 (1.5h) [CHO]; –13 (1.5h) [pl]
Th –19 (CHO); –20 (pl) –8 (1.5h) [CHO]; –11 (1.5h) [pl]
Ts –19 (CHO); –12 (pl) –12 (1.5h) [CHO]; –15 (1.5h) [pl]
B cell –20 (CHO); –16 (pl) NC (1.5h) [CHO]; –12 (1.5h) [pl]
NK –50 (CHO); –27 (pl) –53 (1.5h) [CHO]; –40 (1.5h) [pl]
NKCA –67 (CHO); –72 (pl) –73 (1.5h) [CHO]; –43 (1.5h) [pl]
Kappel et al.[143] n = 8; cycled for 60 min at Leu +90 (cycle); +58 (EP) +113 (2h) [cycle]; +44 (2h) [EP]
75% V̇O2max; received EP Lym +104 (cycle); +39 (EP) +43 (2h) [cycle]; +13 (2h) [EP]
infusion over 60 min Neu +78 (cycle); +75 (EP) +243 (2h) [cycle]; +93 (2h) [EP]
separately
Nieman n = 22 marathon runners Mon +25 (run); NC (con) +256 (3h) [run]; –10 (3h) [con]
et al.[144] ran for 2.5h on a treadmill Lym +9 (run); –4 (con) –41 (1.5h) [run]; –NC (1.5h) [con]
at 70–75% V̇O2max; n = 10 NK +51 (run); –16 (con) –60 (1.5h) [run]; –12 (1.5h) [con]
Sports Med 2006; 36 (1)

inactive control subjects NKCA ET 40 : 1 +4 (run); –6 (con) –40 (1.5h) [run]; +4 (1.5h) [con]

Lim & Mackinnon

NKCA ET 20 : 1 +6 (run); –14 (con) –45 (1.5h) [run]; –4 (1.5h) [con]
NKCA ET 10 : 1 +4 (run); –20 (con) –54 (1.5h) [run]; –14 (1.5h) [con]

Continued next page

 2006 Adis Data Information BV. All rights reserved.
Table II. Contd
Study Study design
Nieman et al.[145] n = 30 marathon runners
ran 2.5h on a treadmill at
75–80% of V̇O2max. n- =
17 consumed CHO; n = 13
consumed placebo
Mixed intensity
Gabriel et al.[146] n = 16 subjects cycled at
85% and 100% of
anaerobic threshold until
exhaustion
Kargotich n = 8 performed interval
et al.[147] swim at 70% and 95% of
maximal exercise intensity
on separate days
Tvede et al.[148] n = 6 subjects cycled at
25%, 50% and 75%
V̇O2max on separate
occasions
Nieman et al.[149] n = 10 subjects ran 2.5h at
50% and 80% V̇O2max on
2 separate occasions
Nieman et al.[150] n = 10 subjects ran at 50%
and 80% V̇O2max for 45
Sports Med 2006; 36 (1)
min on separate days
Intense Training, Immune Response and Heat Stroke
Immune cell type and Post-exercise ≥1h post-exercise
functions (post – pre) [%] (>1h post – pre) [%]
Leu +100 (CHO); +214 (pl) +182 (3h) [CHO]; +257 (3h) [pl]
Mon +21 (CHO); +62 (pl) +66 (3h) [CHO]; +62 (1.5h) [pl]
Lym +5 (CHO); +33 (pl) +24 (1.5h) [CHO]; –26 (3h) [pl]
NKCA ET 40 : 1 +6 (CHO); +119 (pl) –33 (1.5h) [CHO]; –31 (1.5h) [pl]
NKCA ET 20 : 1 +13 (CHO); +22 (pl) –45 (1.5h) [CHO]; –39 (1.5h) [pl]
NKCA ET 10 : 1 +19 (CHO); +39 (pl) –48 (1.5h) [CHO]; –42 (1.5h) [pl]
Gra NC (85%); +2 (100%) +32 (2h) [85%]; +36 (2h) [100%]
Mon +6 (85%); –6 (100%) –22 (2h) [85%]; –34 (2h) [100%]
Lym +2 (85%); NC (100%) –45 (2h) [85%]; –66 (2h) [100%]
T cell –10 (85%); –14 (100%) NC (2h) [85%]; NC (2h) [100%]
NK +48 (85%); +68 (100%) –46 (1h) [85%]; –40 (1h) [100%]
B cell –19 (85%); –21 (100%) +27 (1h) [85%]; +28 (1h) [100%]
Leu +16 (70%); +91 [95%] –NC (2.5h) [70%]; –42 (2.5h) [95%]
Mon +16 (70%); +115 [95%] –13 (2h) [70%]; –11 (1h) [95%]
Lym +14 (70%); +133 [95%] –30 (1h) [70%]; –42 (1h) [95%]
T cell –10 (70%); +77 [95%] –28 (0.5h) [70%]; –47 (2.5h) [95%]
B cell –18 (70%); +42 [95%] –37 (0.5h) [70%]; –48 (2.5h) [95%]
NK +74 (70%); +426 [95%] –41 (2.5h) [70%]; –46 (1h) [95%]
Neu +8 (70%); +58 [95%] –14 (2.5h) [70%]; +120 (2.5h) [95%]
T cell –23 (25%); –17 (50%); –26 (75%) –13 (25%); –6 (50%); –17 (75%)
NK +30 (25%); +113 (50%); +83 (75%) –30 (25%); –25 (50%); –8 (75%)
B cell NC (25%); –NC (50%); –29 (75%) NC (25%); NC (50%); –29 (75%)
Lym pr (PHA) –10 (25%); –26 (50%); –37 (75%) +10 (25%); +50 (50%); +8 (75%)
Leu +15 (50%); +52 (80%) +9 (3.5h) [50%]; +70 (2h) [80%]
Mon +27 (50%); +40 (80%) –15 (1h) [50%]; –5 (1h) [80%]
Lym +8 (50%); +68 (80%) –41 (2h) [50%]; –58 (2h) [80%]
T cell +3 (50%); +53 (80%) –40 (2h) [50%]; –57 (2h) [80%]
Th NC (50%); +39 (80%) –36 (2h) [50%]; –52 (2h) [80%]
Ts +7 (50%); +74 (80%) –44 (2h) [50%]; –62 (2h) [80%]
NK +50 (50%); +152 (80%) –66 (2h) [50%]; –79 (2h) [80%]
B cell NC (50%); +64 (80%) –24 (1h) [50%]; –40 (2h) [80%]
Neu +21 (50%); +48 (80%) –52 (3.5h) [50%]; +207 (2h) [80%]
Mon +49 (50%); +40 (80%) –15 (1h) [50%]; –5 (1h) [80%]
Lym +8 (50%); +68 (80%) –41 (1h) [50%]; –58 (2h) [80%]
T cell –5 (50%); –8 (80%) +3 (1h) [50%]; +5 (1h) [80%]
NK +36 (50%); +50 (80%) –39 (2h) [50%]; –56 (1h) [80%]
B cell –10 (50%); –3 (80%) +30 (2h) [50%]; +44 (2h) [80%]
Continued next page
51
52 Lim & Mackinnon

response after intense exercise may reflect compro-

leukocyte; Lym = lymphocyte; Lym pr = lymphocyte proliferation; Mon = monocyte; NC = no change; NE = norepinephrine; NKCA = natural killer cell cytotoxic activity; Neu =
B cell = B lymphocyte; CHO = carbohydrate; con = control; Con A = Concanavalin A; dex = dexamethasone; EP = epinephrine; Gra = granulocyte; hyd = hydrocortisone; Leu =

neutrophil; NK = natural killer cell; PHA = phytohaemagluttanin; phago = phagocyte or phagocytic; pl = placebo; PWM = pokeweed mitogen; rep = repetition; RM = repetition
mised anti-LPS activities. If so, athletes performing
prolonged intense exercise may have reduced capa-
bility to scavenge and neutralise LPS translocated
during exercise and heat stress, which will increase
the risk of endotoxaemia-driven heat stroke and
(>1h post – pre) [%]

NC (sal)
NC (sal)
+6 (sal)
–4 (sal)

–3 (sal)
reduce heat tolerance.
≥1h post-exercise

maximum; sal = saline; Th = T-helper cell; Ts = T-supressor cell; V̇O2max = maximum oxygen consumption; V̇O2peak = peak oxygen consumption.
7.2 Chronic Immune Response to Exercise
(NE);
(NE);

(NE);
(NE);
(NE);

Epidemiological studies suggest that prolonged

+117
+53
+18

+15
+18

+29
+32
–35
–28
–46
–14

–10

–11

intense exercise increases the risk of upper respira-

tory tract infection (URTI).[154-157] For example, in
the 2 months before the Los Angeles Marathon,
43.2% of runners sampled (n = 2311) reported at
least one bout of URTI; 12.9% of those who were
well before the race experienced symptoms of URTI
in the week after the race.[158] Two other studies
reported that 28–33% of runners had symptoms of
+220 (NE); +17 (sal)
+42 (NE); +12 (sal)
+40 (NE); NC (sal)
+33 (NE); NC (sal)

+39 (NE); NC (sal)

URTI in the 2 weeks following a 56km race; these

(post – pre) [%]

rates were significantly higher than in non-athlete

Post-exercise

control subjects (2.9–15.3%) who lived in the same

household as runners but did not participate in the
+200
+100

+225
+80

+58

+71
+65
+50

race.[155,156]
Other researchers have directly observed long-
term adaptation of the immune system to exercise by
imposing an exercise regime over a period of time.
For example, 4 weeks of anaerobic training and
Immune cell type and

8–15 weeks of moderate intensity aerobic training

did not significantly change immune cell concentra-
Lym pr (PHA)

tions and functions in untrained, middle-aged to

functions

elderly subjects.[131,159-161] In trained runners, no sig-

B cell
T cell
Mon

Mon
Lym

Lym
Neu

Neu

nificant changes in the capacity of neutrophils to

Leu

Leu
NK

NK

produce reactive oxygen species were observed af-

subjected to NE (1 mg/mL)

ter 800km of running during a 1-month training

and sal infusion over 2wk
performed squat exercise

camp.[162] In contrast, elite swimmers undergoing 7

at 65% 1RM, at 1 rep/6
n = 10 male subjects

months,[121] but not 12 weeks,[163] of intensive train-

n = 8 subjects were
sec until exhaustion

ing exhibited a 57% reduction in NK cell concentra-

Study design

tion and 35% reduction in NK cell proportion of

lymphocyte cells. Long-term aerobic training en-
interval

hanced NKCA and lymphocyte proliferative re-

Other exercise/interventions

sponses in the elderly, compared with age-matched

counterparts who had undergone 12 weeks of aero-
bic training.[161] These results suggest that short-
term (4-week) high-intensity and medium-term
Nieman et al.[151]

Kappel et al.[152]
Table II. Contd

(8–15 weeks) moderate-intensity training do not

significantly alter the immune system. High-intensi-
ty training for >6 months may reduce NK cell con-
Study

centration. However, exercise habits that are sus-

 2006 Adis Data Information BV. All rights reserved. Sports Med 2006; 36 (1)
Intense Training, Immune Response and Heat Stroke
tainable over the long term (years) appear to en-
hance NK and lymphocyte cell functions.[161]
7.3 Opportunistic Infection
The ‘open-window’ hypothesis suggests that the
immune system is suppressed for a period of time
after intense exercise[129,130,164] and that dormant
pathogens (especially viruses) in the body can gain a
foothold in the body during the ‘open-window’ peri-
od, thus increasing the likelihood of an infec-
tion.[12,15,129,130,165,166] The period following each ex-
haustive bout of exercise might increase the vulnera-
bility to opportunistic infection.[129,130,165] An
existing infection is likely to induce a higher inflam-
matory and pyrogenic response to LPS and a lower
anti-LPS capacity.[10,11,30,116,167] Heat tolerance may
be compromised when exercise is performed while
harbouring a sub-clinical infection.[35,168] The lack
of overt symptoms in sub-clinical infections does
not allow the athlete to take specific precautions
against conditions that might arise from the infec-
tion, including heat stroke.[35] Increased concentra-
tions of inflammatory and pyrogenic cytokines in
the presence of an infection during intense exercise
may increase the athlete’s risk of heat stroke. The
infection may further reduce the responsiveness of
the body’s defence against translocated LPS.[10,11,116]
8. The Role of Pro-Inflammatory
Cytokines in Heat Stroke
Cytokines are defined as ‘a diverse family of
intercellular molecules that exerts important influ-
ences on inflammatory and immune responses or
haematopoiesis’.[169] Cytokines are generally cat-
egorised into pro- or anti-inflammatory cytokines.
Pro-inflammatory cytokines include IL-1α and -1β,
IL-2 and TNFα.[169,170] Anti-inflammatory cytokines
include IL-6, IL-10, IL-1 receptor antagonist (ra),
and soluble TNF-receptor (sTNFr) 1 and 2.[169,171]
The pro- and anti-inflammatory cytokines counter-
regulate each other in sequence to maintain homeo-
stasis of the cytokine milieu.[20,169,172] The anti-in-
flammatory cytokine, IL-6, induces pyrogenesis to-
gether with IL-1 and TNFα.[117,173]
Both neutrophils and monocytes are key
synthesisers of inflammatory cytokines (e.g. IL-1
and interferon [INF]-α) during local inflammation
 2006 Adis Data Information BV. All rights reserved.
53
and tissue repair.[20,167,169,172,174,175] Inflammatory
cytokines induce the synthesis of IL-6 and pros-
taglandin (PG)E2, both of which have anti-inflam-
matory effects. PGE2 inhibits the biological activity
of IL-1[174] and TNFα.[176] IL-6 stimulates the re-
lease of other anti-inflammatory cytokines (IL-10,
IL-1ra, sTNF-r1, and sTNF-r2) and proteins (e.g. C-
reactive protein) by the liver.[171] Together, these
anti-inflammatory cytokines and proteins counter-
regulate the pro-inflammatory effects of IL-1 and
TNFα.[117,169] This process of pro- and anti-inflam-
matory responses during tissue injury and infection
is known as the acute phase response, which is
targeted at localised tissue repair and preserva-
tion.[171,177]
8.1 Cytokine Response During Heat Stroke
Whereas heat-induced endotoxaemia triggers the
onset of heat stroke, the SIR, which is activated by
the increasing level of circulating LPS, drives the
clinical progression to heat stroke (figure 2). Endo-
toxin is a potent inducer of neutrophils and mono-
cytes, which, in turn, produce cytokines, including
TNFα,[30,116,178] IL-6[117,179] and IL-1;[116,118] TNFα
release also induces IL-1 synthesis.[60,180] IL-1 and
TNFα promote inflammation and induce fe-
ver.[30,173] As mentioned in section 8, the synthesis
and actions of IL-1 and TNFα are counter-regulated
by anti-inflammatory cytokines, such as IL-10,
IL-1ra, sTNF-r1 and -r2, and IL-6.[169,171,181]
Heat stroke increases the concentrations of pro-
(IL-1 and TNFα) and anti-inflammatory cytokines
(IL-6, IL-1ra, and IL-10) in humans[8,60,182-184] and
animals.[185-187] This concomitant increase in both
classes of cytokines indicates activation of conflict-
ing immune processes. Whereas inflammatory
cytokines help control endotoxaemia, their activa-
tion in the central circulation leads to other compli-
cations such as systemic inflammation and coagula-
tion. At the same time, inhibiting the activities of
these cytokines allows endotoxaemia to progress.
During heat stroke, the body’s systems act to
counteract the immediate threat of endotoxaemia,
favouring the pro-inflammatory cytokines, and sep-
sis, systemic inflammation, DIC and MOF may
result.[184] This sequence of systemic inflammation
highlights the consequences when a local inflam-
matory response occurs in the central circula-
Sports Med 2006; 36 (1)
54 Lim & Mackinnon

Intense exercise
Tissue damage

Anti-LPS is ¯ Th1 and Th 2 ­

suppressed
Macrophage

Gut tissue Inflammatory and

ischaemia and hypoxia pyrogenic cytokines

Macrophage
Activation of LPS and neutrophil Augmentation of
anti-LPS translocation inflammatory and
pyrogenic cytokines
Inhibits rise Anti-LPS <
in plasma LPS plasma LPS

Clearance of Endotoxaemia
LPS by liver

Fever Systemic Hypotension ­ Vascular

IL-1, IL-6, inflammation IL-1b permeability
TNFa IL-1 and TNFa TNFa

Heat storage · Systemic coagulation Haemorrhagic shock

· Necrosis
· Cell death
· Organ damage
Fig. 2. Cytokine and lipopolysaccharide responses during intense exercise. Intense exercise suppresses anti-lipopolysaccharide antibodies
(anti-LPS) and T-helper cell 1 (Th1) immunity, and promotes LPS translocation and T-helper cell 2 (Th2) immunity. The suppression of anti-
LPS facilitates the accumulation of LPS in the circulation, which induces an increase in inflammatory and pyrogenic cytokines. The
suppression of Th1 and promotion of Th2 immunity, along with exercise-induced muscle tissue damage also induce the synthesis and
release of inflammatory and pyrogenic cytokines. These cytokines promote pyrogenesis, systemic inflammation, increased vascular
permeability and hypotension, which contribute to the symptoms of heat stroke. IL = interleukin; TNFα = tumour necrosis factor-α.

tion.[117] Whereas local inflammation promotes tis-
sue repair, the activation of inflammatory cytokines
in the circulation leads to systemic inflammation,
resulting in shock.
During heat stroke, circulating endotoxins acti-
vate the inflammatory response in the circulation,
leading to systemic inflammation and shock. Heat
stroke patients continue to exhibit elevated levels of
pro-inflammatory cytokines even after recovery.[184]
Besides promoting inflammation, TNFα induces ac-
idosis, widespread necrosis, and vasodilation, which
are consistent with the clinical presentation of heat
stroke.[5,34,39,173] TNFα also causes the loss of plas-
ma volume by increasing vascular permeability,
leading to haemorrhagic shock.[117] Blocking the
TNFα in gene-knockout mice prevented the induc-
tion of acute-phase proteins by endotoxins,[188] indi-
cating that TNFα plays an orchestrating role in the
clinical progression of heat stroke.
IL-1 induces hypotension, which destabilises the
cardiovascular system[185,187] and stimulates the re-
lease of neutrophils through IL-8 or directly from
the bone marrow, which promotes inflamma-
tion[173,174,189] (e.g. inhibition of IL-1 by IL-1ra in
rats undergoing heat stroke increased survival by
5.4-fold compared with rats treated with saline solu-
tion).[190] This implies that IL-1 and TNFα act syner-
gistically in the acute-phase response during heat-
induced endotoxaemia.
Although IL-6 directly inhibits the expression of
IL-1 and TNFα,[171,191] it also induces fever, as do
the other pro-inflammatory cytokines.[173,191] IL-6
may function as the ‘messenger’ between the site of
inflammation and the brain.[180,192] IL-6 is produced

 2006 Adis Data Information BV. All rights reserved. Sports Med 2006; 36 (1)
Intense Training, Immune Response and Heat Stroke
in response to IL-1 and TNFα, and its concentration
is positively correlated with the severity of heat
stroke[8] and sepsis.[173] The regulation of pro- and
anti-inflammatory cytokines in response to endotox-
aemia is critical in the clinical progression of heat
stroke.
8.2 Exercise-Induced Cytokine Release and
the Mechanism of Heat Stroke
Strenuous exercise increases plasma concentra-
tions of IL-1, IL-6 and TNFα. For example, running
a marathon, or running or cycling for 1–6 hours at
60–75% V̇O2max significantly increases concentra-
tions of plasma IL-1α and -1β (up to 14.75-fold),
TNFα (1.3- to 1.9-fold) and IL-6 (1.6- to
>100-fold).[171,181,193-198] Exercise usually causes less
of an increase in plasma cytokine concentrations
than heat stroke does. However, the two conditions
induce a similar pattern of cytokine release (i.e.
increases in IL-1, TNFα and IL-6). The sub-clinical-
ly increased levels of IL-1, IL-6 and TNFα during
intense exercise indicate a higher basal level of
inflammatory cytokines, which may activate the SIR
at the onset of endotoxaemia. Elevation of circulat-
ing IL-1, IL-6 and TNFα levels may also impair
central temperature regulation under heat stress
through their pyrogenic effects, suggesting that the
cytokine profile induced by intense exercise may
serve as a precursor of the cytokine response during
heat stroke.
9. T-Helper Cell 1 and 2 (Th1/
Th2) Balance
Exercise-induced immune suppression has been
attributed to a shift in the balance between the T cell
subsets (Th1 and Th2 cells).[20] Th1 cells function
primarily in cell-mediated immunity, promoting
phagocytic activities against intracellular patho-
gens.[199] Th2 cells function in humoral immunity
and are closely associated with B cells.[199] Intense
endurance exercise suppresses Th1 immunity, but
does not change Th2 immunity.[200,201] The suppres-
sion of Th1 immunity may be specific to activities
involving long-distance running, which causes more
physical trauma[108] and damage[22,27,104,105] to the
intestines and muscle tissues[202] than cycling.[203]
 2006 Adis Data Information BV. All rights reserved.
55
This might stimulate greater production of Th2
cytokines, such as TNFα and IL-6.[4,112]
9.1 Possible Roles of Th1 and Th2 Immunity in
the Mechanism of Heat Stroke
Th1 is associated with increased levels of IL-2,
IL-12, INF-γ and TNFβ, and the suppression of Th1
immunity increases the risk of an infection, which
may reduce the ability of the immune system to
scavenge and remove circulating LPS. Th2 is associ-
ated with the release of IL-4, IL-5, IL-6, IL-10,
IL-13 and TNFα,[20] which play important roles in
the SIR.
Heat stroke and strenuous exercise are associated
with the up-regulation of Th2 cytokines (IL-1, IL-6
and TNFα),[8,60,171,182,184,204] which is attributed to
muscle tissue damage and its ramifications.[20,167]
This is consistent with the post-exercise neutrophilia
documented after strenuous exercise,[136,137,140,141,143]
presumably as part of the tissue repair process.
Rhabdomyolysis, the extreme of exercise-induced
tissue damage, also occurs in heat stroke pa-
tients.[38,184,205-208] This evidence implies that exer-
cise-induced tissue damage contributes to cytokine
involvement in the development of heat stroke. The
up-regulation of Th2 immunity is also consistent
with the presence of endotoxaemia, as humoral im-
munity would be a more appropriate response to
septicaemia than would cell-mediated immunity.
We postulate that exercise-induced tissue damage
and endotoxaemia stimulate the up-regulation of
Th2 cytokines, similar to that in heat stroke patients.
The dominance of Th2 cytokines with intense exer-
cise suggests that the immune system is more in-
clined towards a state of inflammation (IL-1 and
TNFα) and pyrogenesis (IL-1, TNFα and IL-6),
which may become exaggerated during heat stroke.
10. Immune Disturbance and
Heat Stroke
Reduced heat tolerance may be associated with
immune disturbances,[34,53,87,116] although this has
not been extensively studied. In this review, the term
‘immune disturbance’ describes the immune re-
sponses during intense exercise that might contrib-
ute to heat intolerance. ‘Immune suppression’ refers
to the down-regulation of immune cell concentra-
Sports Med 2006; 36 (1)
56 Lim & Mackinnon

Table III. Immune disturbances during intense exercise and its influence on heat tolerance
Immune parameters Regulation during Effects on heat tolerance
intense exercise
Plasma endotoxin ↑ Causes endotoxaemia; triggers the mechanisms of heat stroke
Triggers the release of macrophages, neutrophils and inflammatory/pyrogenic cytokines
Inflammatory/pyrogenic ↑ Drives systemic inflammation, vascular coagulation, necrosis and tissue-cell death
cytokines (IL-1, IL-6 and Promotes systemic hypotension
TNFα) Promotes haemorrhagic shock
Promotes pyrogenesis and heat storage
Th2 immunity ↑ Promotes pro-inflammatory and pyrogenic cytokines
Th1 immunity ↓ Inhibits anti-inflammatory cytokines
Increases the risk of an infection
Anti-LPS antibodies (IgG ↓ Reduces surveillance and scavenging of endotoxins
and IgM) Reduces tolerance against plasma endotoxins
Lymphocyte T- and ↓ Indirectly reduces the concentration of anti-LPS antibodies when responding to plasma
B-cells endotoxins
IL = interleukin; LPS = lipopolysaccharide; Th1 = T-helper cell 1; Th2 = T-helper cell 2; TNFα = tumour necrosis factor-α; ↓ indicates
decrease; ↑ indicates increase.

tions and functions, which do not directly affect heat
tolerance. Immune disturbance includes an increase
in the concentration of plasma endotoxins (endotox-
aemia), up-regulation of inflammatory cytokines
and Th2 cells, and down-regulation of Th1 cells and
anti-LPS antibodies (table III). Because these im-
mune responses threaten homeostasis of the immune
system, the term ‘immune disturbance’ is more ap-
propriate to describe their roles in exercise and heat
tolerance.
The American College of Sports Medicine rec-
ommends that physical activities should be avoided
after a recent bout of infectious illness because it
increases the risk of heat-related illness.[168] Sleep
deprivation and fatigue, which suppress immune
function,[129,165,199,209] have been identified as risk
factors in soldiers who died of heat stroke.[34,53] Pre-
existing or sub-clinical infection has also been iden-
tified as a contributing factor to repeated bouts of
transient heat intolerance in the military.[35] Among
military recruits, 16–18% of those who experienced
heat stroke showed symptoms of URTI before be-
coming ill.[33,53] The association between heat stroke
and immune disturbance in these recruits may be
stronger, since the data did not include recruits with
pre-symptomatic infections. Thus, there appears to
be a plausible positive relationship between exer-
cise-induced immune disturbances and vulnerability
to heat tolerance despite the lack of experimental
evidence.
We hypothesise that immune disturbances during
intense exercises and heat stroke exists in the same
continuum. This is supported by data on athletes and
soldiers who experienced heat stroke.[33,70,73,205]
When trained individuals succumb to heat stroke, it
is unlikely to be because of a lack of fitness or
acclimatisation because they would have been ex-
posed to and have tolerated the same physical stress
and heat stress before. These heat stroke victims
would have trained intensely for an extended period
before the bout of heat stroke and would have exper-
ienced some degree of immune disturbances similar
to that in heat stroke; such immune disturbances
may lead to transient heat intolerance.[35]
At present, there is no empirically based model to
explain the occurrence of heat stroke in well trained
individuals performing usual exercise. Most re-
searchers suggest that heat stroke during exercise
arises from hot weather conditions, dehydration, and
lack of acclimatisation,[1,33,87,168,210,211] although
there is little supporting empirical evidence. After
prolonged exercise, healthy athletes may exhibit
Tc[78,80-82,90] similar to that documented in heat
stroke patients[74,87] but without any symptoms of
heat stroke. This suggests that well trained individu-
als can normally tolerate a high level of heat stress
and that heat stroke may result from transient heat
intolerance, possibly because of a transient altera-
tion of the physiological state. Prolonged intense
exercise may lead to a state of extended immune
disturbance that is qualitatively similar to, but of a
lower magnitude than, heat stroke;[4,28-30] these im-
mune disturbances may transiently reduce heat tol-
erance.

 2006 Adis Data Information BV. All rights reserved. Sports Med 2006; 36 (1)
Intense Training, Immune Response and Heat Stroke 57

11. The Dual Pathway Model of
Heat Stroke
Disturbance of immune function during heat
stroke shares some common aspects with that aris-
ing in response to intense exercise.[24,116] Such com-
mon responses include endotoxaemia, up-regulation
or over-expression of pro-inflammatory cytokines
and Th2 immunity, and down-regulation of Th1 im-
munity and anti-LPS mechanisms. The ‘dual path-
way model’ integrates the current understanding of
the pathology of heat stroke and evidence of im-
mune disturbances, endotoxaemia, and GI distur-
bances associated with intense exercise (figure 3).
This model suggests that endotoxaemia (heat sepsis)

Prolonged Pyrogenic cytokines Exercise and heat stress

exposure to promote heat storage
intense training
1
­ Heat storage
Th1 immunity ¯ ¯
Th2 immunity
­ GI stress

­ Intestinal epithelial
Blunted immune Exercise permeability
Immune
response and heat
disturbance
to pathogens stress

LPS migrates to liver

Suppressed immune via portal circulation
surveillance for LPS

2
LPS overwhelms LPS neutralised
the liver in liver/circulation
Exercise
Sub-clinical
Pathogen and heat
infection
stress Endotoxaemia Exercise continues

Inflammatory Acute phase response

cytokines exaggerate IL-1 and TNFa Voluntary/involuntary
3 acute phase response
exercise cessation

Systemic inflammatory
response; DIC, MOF:
heat stroke
Heat stroke caused by direct effect of
heat at very high Tc, when endotoxaemia
is tolerated or prevented
4

Fig. 3. The dual pathway model of heat stroke. Right side of model (thermoregulation component): exposure to intense exercise increases
heat storage and permeability of gut epithelial tissue. This promotes lipopolysaccharide (LPS) translocation from the gut into the portal
circulation, which transports the LPS to the liver to be neutralised and removed from the body. Exercise continues until voluntary cessation
or exhaustion if the anti-LPS system is able to cope with the magnitude of LPS translocation. When the liver is overwhelmed by LPS, LPS
leaks into the central circulation, resulting in endotoxaemia, which can trigger the acute phase response, resulting in heat stroke. Left side of
model (immune-regulation component): prolonged exposure to intense exercise suppresses cell-mediated T-helper cell 1 (Th1) immunity,
reduces the immune response to pathogens, and increases the risk of an infection. These exercise-induced immune disturbances can
contribute to heat storage and endotoxaemia by promoting pyrogenesis (1) and inflammation (3), and suppressing immune surveillance
against LPS (2). When endotoxaemia can be tolerated or prevented, continuing exercise and heat exposure will elevate Tc to a point where
heat stroke can occur via the direct effect of heat on tissue cells (4). DIC = disseminated intravascular coagulation; GI = gastrointestinal; IL =
interleukin; MOF = multi-organ failure; Tc = core temperature; Th2 = T-helper cell 2; TNFα = tumour necrosis factor-α; ↓ indicates decrease;
↑ indicates increase.

 2006 Adis Data Information BV. All rights reserved. Sports Med 2006; 36 (1)
58
occurring under heat stress is the primary pathway
for heat stroke.[3,5,7] In instances where endotox-
aemia is prevented or well tolerated, heat stroke may
occur through the secondary pathway, which is driv-
en by the direct effect of heat on organ tissues (heat
stroke).[62,63,124] This model is based on exposure to
multiple bouts of exercise over an extended period
of time; chronic and acute immune disturbances act
synergistically with each bout of intense exercise to
compound the risk of heat stroke.
The dual pathway model of heat stroke (figure 3)
builds on the endotoxaemia model of heat stroke by
integrating immune disturbances induced by intense
exercise with the endotoxaemia pathway. The pri-
mary thesis of this model is that heat intolerance is
transient and arises when intense exercise is under-
taken under a state of immune disturbance. This
model includes both the thermoregulation and im-
mune-regulation components. The thermoregulation
component recognises that some degree of LPS
leakage occurs routinely during intense exercise and
heat stress, but the circulating LPS is cleared effi-
ciently by a normally functioning immune system.
This allows the exercise to proceed even when Tc is
substantially elevated, as observed in healthy run-
ners.[77-83] The exposure to both exercise and heat
continues until exercise stops voluntarily or when
the anti-LPS system starts to fail and LPS starts to
accumulate in the central circulation.
The immune-regulation component recognises
that exposure to multiple bouts of intense exercise
compromises Th1 immunity,[20,169] suppresses im-
mune cell concentration and function,[15,129,164,166,212]
and anti-LPS mechanisms,[10,28-30] (discussed in sec-
tions 7 and 8). A decrease in Th1 immunity and a
suppressed immune system increases the likelihood
of an infection.[20,213] Muscle tissue damage sus-
tained from previous exercise bouts and the exis-
tence of an infection (including sub-clinical infec-
tion) are associated with an increase in inflammato-
ry cytokine concentration.[167,171,172,176] During
exercise and heat stress, these cytokines may com-
pound heat storage through the pyrogenic path-
way[7,66] and cause the thermoregulation pathway to
operate at a faster rate. This process increases LPS
translocation and the likelihood of LPS leakage into
the central circulation. An elevated inflammatory
cytokine level also exaggerates the acute phase re-
 2006 Adis Data Information BV. All rights reserved.
Lim & Mackinnon
sponse to the appearance of LPS in the circula-
tion,[3,5] adding to the inflammatory response. A
suppressed immune system also reduces immune
surveillance against LPS in the portal and central
circulation,[10,30] which increases the opportunity for
endotoxaemia to occur. Athletes who are presented
to the exercise environment with these immune dis-
turbances are likely to have transient heat intoler-
ance.
12. Conclusion
The current model of heat stroke suggests that
heat stroke is triggered by hyperthermia but driven
by endotoxaemia. Although the manifestation of
endotoxaemia during heat stress can explain the
central mechanisms of heat stroke, the role of
hyperthermia as the sole trigger of heat stroke re-
mains debatable. The level of Tc reported in heat
stroke patients overlaps with that experienced by
healthy athletes and soldiers during intense exercise
without showing symptoms of heat stroke. Athletes
and soldiers who experienced heat stroke would
have been exposed to the same level of heat and
physical stress before without succumbing to heat
stroke. Evidence from research on the concept of
critical Tc (about 40ºC in humans) as the trigger of
central fatigue suggests that the critical Tc may
function as a defensive mechanism against heat
stroke. Animal studies also show that at Tc <43.5ºC,
heat stroke can be prevented by blocking the effects
of LPS; at Tc >43.5ºC, heatstroke can occur through
the direct effects of heat on tissue cells, without the
occurrence of endotoxaemia. Therefore, the physio-
logical significance of Tc in the pathology of heat
stroke shifts from that of a protector to that of a
facilitator of heat stroke as Tc shifts from about
40ºC to >43.5ºC.
The evidence presented in this review supports
the argument that heat stroke is driven by two con-
nected pathways. The primary pathway is facilitated
by heat stress but triggered and driven by endotox-
aemia. When endotoxaemia can be prevented or
tolerated, continuing exercise and heat exposure ele-
vates Tc to a point where heat stroke can occur
through a secondary pathway that is triggered and
driven by the direct effects of heat on tissue cells.
This evidence supports the argument that heat intol-
erance is transient and results from a transient shift
Sports Med 2006; 36 (1)
Intense Training, Immune Response and Heat Stroke
in physiological state. We postulate that this shift in
physiological state can be induced by immune dis-
turbance resulting from intense exercise training.
Immune disturbance includes the suppression of
immune cell count and function, suppression of cell-
mediated immunity, GI mucosal damage and symp-
toms (e.g. vomiting, diarrhoea and bloody stool),
and elevated inflammatory and pyrogenic cytokines.
The hypothetical pathway through which this im-
mune disturbance may contribute to heat stroke is
proposed in the dual pathway of heat stroke. This
model of heat stroke recognises that LPS routinely
leaks into the circulation during intense exercise and
heat stress, but the circulating LPS is efficiently
removed through the RES of the liver in a normally
functioning immune system. This allows the exer-
cise and heat exposure to continue until exercise
performance is stopped voluntarily or when the LPS
starts to accumulate in the circulation because of a
failing anti-LPS system. A period of intense exer-
cise training may compromise the anti-LPS system
and reduce the ability of the RES to remove circulat-
ing LPS during intense exercise, thus reducing heat
tolerance.
The dual pathway model suggests that prolonged
exercise training may compromise the anti-LPS sys-
tem through GI disturbances, which promotes LPS
translocation from the gut to the circulation, eleva-
tion of inflammatory and pyrogenic cytokine level,
suppression of cell-mediated (Th1) immunity and
anti-LPS antibodies, and an increase in the risk of
opportunistic infection. The combined effect of
these immune disturbances reduces heat tolerance
against the primary (endotoxaemic) pathway of heat
stroke. Tolerance against endotoxaemia permits ex-
ercise and heat exposure to continue under an in-
creasing level of Tc, to a point where heat stroke can
occur through the secondary pathway, via the direct
effect of heat on tissue cells.
We have presented evidence to support a new
model to explain the pathology of heat stroke by
integrating information from research in exercise
immunology, the GI responses to exercise, and ther-
moregulation. This model provides a hypothetical
explanation for the inconsistency of hyperthermia as
a trigger of heat stroke and the association between a
compromised immune system and heat intolerance.
This should provide a useful platform for further
 2006 Adis Data Information BV. All rights reserved.
59
research to better understand the complex mecha-
nisms of heat stroke. One question might focus on
whether other avenues, besides the gut, for LPS
translocation are activated by exercise and heat
stress. Gathiram et al.[110] suggested that LPS may
leak into the circulation through lymphatic vessels
during heat stress. Another area of future research is
the transition between the endotoxaemia-driven and
heat-driven pathways. We believe that there is an
overlap between these two pathways during the tran-
sition, but at present there is no information to
identify its mechanisms. Finally, one practical appli-
cation would be to determine whether pharmaceuti-
cal and nutraceutical products that enhance immune
function and cleanse the gut of bacteria might im-
prove heat tolerance. Information from such re-
search will contribute significantly to the refinement
of the current paradigm in heat stroke research and
management.
Acknowledgements
The authors are grateful to the Defence Science Organisa-
tion National Laboratories, Singapore, for supporting the
preparation of this manuscript. The views expressed in this
manuscript are those of the authors. They do not represent the
views of the Ministry of Defence, Singapore.
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Correspondence and offprints: Chin Leong Lim, Military
Physiology Laboratory, Defence Medical and Environmen-
tal Research Institute, 27 Medical Drive #10-00, DSO Kent
Ridge Building, 117510, Singapore.
E-mail: limcl@dso.org.sg
Sports Med 2006; 36 (1)