Sleep is clearly adaptive and much effort has been directed at determining its functions1,2,93,94
. As we have reviewed, sleep is altered during infection. Infection increases the concentrations of cytokines, including IL-1, and the release of neurotransmitters, including 5-HT, in the brain, and interactions between IL-1 and 5-HT contribute to the regulation of sleep. We are beginning to understand how infection induces these changes, but it remains unknown why sleep is altered during sickness. We propose that altered sleep during infection, as a component of the acute-phase response and sickness behaviour, promotes recovery.
Is there any evidence to support the hypothesis that altered sleep during infection is a determinant of clinical outcome? Although it did not directly test this hypothesis, at least one study suggests that this might indeed be the case. Toth and colleagues95
retrospectively analysed data derived from long-term studies of bacterial or fungal infection-induced alterations in sleep in rabbits. The authors calculated for each animal a cumulative sleep-quality score that reflected both the duration and the intensity of NREM sleep. This approach allowed stratification of the outcome on the basis of whether the animals had high or low sleep-quality scores (good sleep or poor sleep, respectively) during the course of the infection. These cumulative sleep-quality scores were then correlated with the infective dose of the pathogen, multiple clinical parameters and the outcome. Analyses revealed that the infective dose of the pathogen differed between animals, and animals that received a higher pathogen dose generally had low cumulative sleep-quality scores. This suggests that the sicker the animal, the more disrupted its sleep. However, and of importance to this discussion, there were individual differences in the fates of animals that received the same infective dose: animals that survived had higher sleep-quality scores than animals that died. Although — as with any study that reports associations — this study did not demonstrate causality, and although it has yet to be repeated, these data are consistent with the hypothesis that dynamic changes in sleep during infection aid recovery.
How might infection-induced alterations in sleep promote recovery? We propose that they facilitate the generation of fever. In this view it is fever that imparts survival value, and fever could not develop during infection if sleep architecture was not altered. This hypothesis is based on two extensive bodies of literature, one describing links between sleep and thermoregulation96
and the other indicating that fever is adaptive97
The regulation of body temperature is coupled to sleep96
: superimposed on the circadian rhythm of body and brain temperature are arousal state-dependent temperature changes (). For example, brain and body temperature decrease during NREM sleep; the longer and more consolidated the NREM-sleep episode, the greater the decrease in brain or body temperature, until the regulated asymptote is reached. By contrast, brain temperature increases rapidly during REM sleep96,98
(). In addition, thermoregulation is dependent on the sleep–wake state; for example, shivering does not occur during REM sleep96,99
Sleep architecture is altered during fever
Vertebrates and invertebrates develop fever in response to administration of pyrogens (fever inducers) or infection with pathogens. Data demonstrate increased survival when the host develops a moderate fever during bacterial or viral infections97
. The survival value of fever to the host organism is conferred primarily by two mechanisms: facets of immune responses are potentiated at elevated body temperature, and the host environment is directly altered such that conditions for replication of the pathogen become less optimal97,100
Proposed principles by which changes in sleep architecture promote recovery from infection
However, fever is energetically demanding: metabolism must be increased to raise and then maintain body temperature. It has been estimated that the mean increase in metabolism is 13% for every 1°C increase in body temperature100
. Increasing the amount of time spent in NREM sleep reduces the energy expenditure that is associated with competing activities, such as locomotion. But the changes in sleep architecture that occur during infection (suppressed REM sleep and increased but more fragmented NREM sleep) might have additional, fever-promoting benefits: shivering is crucial to the generation of fever but does not occur during REM sleep96
. Perhaps for this reason REM sleep is eliminated during the early stages of fever (). Furthermore, thermoregulatory mechanisms that reduce heat loss complement those involved in heat production (shivering) in the effort to increase body temperature. As heat dissipation normally occurs during NREM sleep, the fragmented nature of NREM sleep during the febrile response () may be viewed as a mechanism to reduce heat loss.
Data demonstrate that fever is adaptive and has evolved to increase survival in response to infection. Although it is unlikely that sleep has evolved solely to support the generation of fever during infection, the alterations in sleep in response to microbial pathogens are exquisitely designed to fulfil this role: the increase in NREM sleep conserves energy; the suppression of REM sleep allows shivering and, therefore, the production of fever; and the fragmentation of NREM sleep reduces heat loss.