Bryant, Penelope A. PhD*†; Curtis, Nigel PhD*†‡
From the *Infectious Diseases Unit, Department of General Medicine, The Royal Children’s Hospital Melbourne; †Murdoch Children’s Research Institute, Parkville; and ‡Department of Paediatrics, The University of Melbourne, Melbourne, Australia.
The authors have no funding or conflicts of interest to disclose.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).
Address for correspondence: Penelope A. Bryant, Department of General Medicine, The Royal Children’s Hospital Melbourne, Flemington Road, Parkville, VIC 3052, Australia. E-mail: email@example.com.
You are more likely to catch a cold if you are tired: fact or fiction? There is in fact a surprisingly large body of evidence to support the widely held belief that sleep deprivation increases susceptibility to infection.1 The link between sleep and the immune system has important implications for both individuals and the population, as there has been a steady decline over the last few decades in individuals’ average duration of sleep.2 Herein we review the evidence that there is a relationship between sleep, immunity and infection, including the small amount of data in children.
Of the 2 phases of sleep, rapid eye movement sleep is thought to be the restorative phase. Nonrapid eye movement sleep, and the slow wave sleep component in particular, is believed to be involved in information processing.
DO INFECTIONS INFLUENCE SLEEP DURATION?
Experimental Infections in Animals and Humans
Studies in both animals and humans show evidence that a variety of viral and bacterial infections lead to increased sleep.3,4 For example, in humans experimentally infected with influenza, sleep duration decreases during incubation and increases during the symptomatic phase.3
Clinical Infections in Adults and Children
Infants recovering from upper respiratory tract infection show impaired arousal from sleep compared with healthy controls, suggesting an explanation for the association between infection and sudden infant death syndrome observed in some studies.5 A recent review of randomized control trials of oseltamivir versus placebo in adults and adolescents with influenza showed a significantly faster return to baseline sleep durations with treatment, supporting the notion that it was the virus that caused increased sleep.6
Sleep has been studied extensively in HIV-infected adults and adolescents compared with healthy controls with widely varying results, only partially explained by the use of different sleep assessment tools and measures of sleep. Children with HIV have less sleep and are more tired than healthy controls.7 A recent study in adolescents found that HIV infection was associated with changes in sleep pattern, with concomitant significant differences in blood cytokine levels.8
Cytokines and Sleep
Cytokine studies have led to the hypothesis that pathogen-induced host immune factors are the means by which infection influences sleep. Studies in both animals and humans have shown different effects of cytokines on sleep, especially TNF, IL-1 and IL-6 (Table, Supplemental Digital Content 1, http://links.lww.com/INF/B690). However, no single cytokine is consistently associated with sleep, and this may explain why different infections are associated with different patterns of sleep disruption.
The regulation of endogenous cytokines during the sleep/wake cycle also provides some intriguing insights. Circadian rhythmicity is clearly an important aspect of sleep, and the paradigm for circadian regulation is the endocrine system. There is a well-recognized relationship between the neuroendocrine and immune systems, and studies suggest that they interact to influence sleep (Fig. 1 and Table, Supplemental Digital Content 1, http://links.lww.com/INF/B690). The same cytokines are involved in both physiological sleep and the effects of infection on sleep.
Because infection generally increases sleep duration, and because cytokines are physiologically regulated during sleep, it has been suggested that sleep is restorative to immune function. Sleep deprivation studies are designed to investigate this hypothesis.
DOES SLEEP DURATION INFLUENCE THE IMMUNE RESPONSE?
Sleep Deprivation Studies in Humans
Animal and human studies show that sleep deprivation has detrimental effects on immune cells and cytokines.1 In humans, numbers of T helper cells and natural killer cells decrease after one night’s sleep deprivation.9 Both endogenous cytokine levels and cytokine responses to lipopolysaccharide stimulation are also affected (Table, Supplemental Digital Content 1, http://links.lww.com/INF/B690).
Although the concept of a single mediator of sleep and infection, “sleepamine,” is attractive, it is more likely that a combination of immune regulatory molecules mediates the relationship between sleep and the immune response necessitating a global approach to investigating this link. A recent study used microarrays to compare global gene expression in volunteers afforded insufficient sleep for 7 nights (mimicking chronic partial sleep loss) with expression in the same individuals after adequate sleep.10 Insufficient sleep led to up- or downregulation of gene expression, loss of circadian rhythmicity and decreased amplitude of circadian-regulated expression. Clusters of genes involved in immune and inflammatory responses, cytokine activity and nuclear factor kappa B signaling peaked in their endogenous expression in the biological day, and sleep deprivation led to loss of circadian rhythmicity and decreased amplitude of expression. Significant increases in interleukin (IL)-6 and IL-1 receptor expression were seen after sleep deprivation, paralleling findings from other studies (Table, Supplemental Digital Content 1, http://links.lww.com/INF/B690).
Clinical Sleep Deprivation
In children, obstructive sleep apnea has been considered by some researchers to provide a clinical scenario in which the effects of chronic partial sleep loss can be investigated.11 Several studies have investigated inflammatory pathways in obstructive sleep apnea, showing increases in plasma proinflammatory cytokines, such as tumor necrosis factor and IL-6.12,13 However, obstructive sleep apnea is not universally thought to be associated with sleep deprivation, and it is difficult to separate the potential confounding effects of hypoxia. The same is true in infective exacerbations in cystic fibrosis: these are associated with decreased rapid eye movement sleep, which resolves with antibiotics.14 Chronic insomnia in adults without hypoxia, however, is also associated with changes in cytokines, including decreased IFN-g levels.15 Chronic fatigue syndrome, which may follow an acute infection, shows disordered sleep architecture with disrupted nonrapid eye movement sleep. Although studies have shown an altered cytokine profile in some individuals with chronic fatigue, including increases in cellular production of tumor necrosis factor and IL-6, whether this is a causal relationship is uncertain.16
IS THE EFFECT OF SLEEP ON THE IMMUNE SYSTEM CLINICALLY RELEVANT?
Functional Effects of Sleep Deprivation
Are the observed effects on the immune response induced by sleep deprivation important in the clinical setting? The immune response to immunization provides an opportunity to investigate this. A key study showed that healthy adults immunized against influenza A during partial sleep deprivation developed antibody titers half the level of those in well-rested controls (level III).17 A single night’s total sleep deprivation has recently been shown to adversely affect antibody titers early in response to H1N1 vaccination in males, although not females (level III).18 Interestingly in both studies the effect was only shown at several days postimmunization and the difference was no longer significant after a few weeks, suggesting both that sleep is important in the early adaptive response and that subsequent restorative sleep reverses the effect. Decreased sleep also lowers the antibody response to hepatitis A (level III)19 and hepatitis B vaccines (level III).20 Conversely, after immunization against hepatitis A, sleep promotes Th1 adaptive responses and immunological memory.19
There have been surprisingly few studies in humans that have directly addressed whether sleep deprivation increases susceptibility to or severity of infections, as they have not investigated the infection rate in the period after sleep deprivation. In addition, most studies have investigated only healthy subjects and only short periods of sleep deprivation. Of greater relevance to society is the chronic partial sleep loss that is typical in shift workers (who in studies report more infections than nonshift workers)21 and also relevant to the population in general. A recent study directly addressed the rate of infection in this circumstance. Volunteers were asked to record their daily sleep duration and efficiency for 14 days and were then quarantined for 14 days and challenged with intranasal rhinovirus (level III).22 Intriguingly there was a “dose-response” relationship, with those individuals who had less than 7 hours average sleep being almost 3 times more likely to develop a cold than those who had 8 hours or more. Poorer sleep efficiency—the proportion of time in bed actually asleep—showed a similar effect, and potential confounding factors were excluded. This is the best evidence yet to support the notion that you are more likely to catch a cold when you are tired.
The effects of chronic partial sleep deprivation may have significant effects on other conditions in which immunity may play a role. Disordered sleep and cytokine abnormalities have also been shown in inflammatory bowel disease and cancer.
In light of the increasing evidence for an effect of sleep, and more importantly the lack of sleep, on the immune system, and some evidence that this might be functionally important, can we do anything about it? On one level, the documented decreasing median sleep duration in the population over the last few decades might be seen as a public health issue. On an individual level, 1 interesting study in patients on hemodialysis showed that cognitive behavioral therapy is more effective than simple sleep hygiene advice in improving sleep disturbance, and at the same time, it reduced plasma C-reactive protein and IL-18.23 This suggests that sleep disturbance and its effects on the immune system are amenable to change.
Recognizing sleep as a crucial component of the immune system not only gives insights into the immune response but also raises awareness about the importance of sleep for society as a whole and for patients. Perhaps as clinicians we should at least recognize the potential detrimental effects of sleep disruption on patients in busy wards and intensive care.
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