Tired and Sick

Sleep serves a vital role in modulation of immunological processes with which it shares regulatory genes and molecules.¹ Multiple loci on various human chromosomes contain genes that affect quantitative aspects of sleep.² Eight loci strongly implicated in sleep regulation contain genes that are also involved in the immune system.² Infections increase the amount and drive for sleep; sleep changes occur not only following exposure to various microorganisms but also to antigenic portions such as muramyl peptides and lipopolysaccharides, most likely by way of stimulation of transcriptional activity of nuclear factor-kB by pro-inflammatory cytokines such as TNF-α and IL-1-β.¹

Sleep appears to modulate immune responses through centrally produced regulatory cytokines.¹ Most data regarding this interaction come from exploring the effects of sleep deprivation on responses to infectious challenges. Animal studies have found that chronic sleep deprivation reduces total leukocyte and monocyte numbers, spleen weight, and complement C3; it increases the immunoglobulin M concentration³ and is associated with an increased rate of bacteremia.⁴ Studies of partially sleep deprived human subjects have found an impaired immune milieu characterized by lower natural killer (NK) cell activity and interleukin-2 production and increased inflammatory markers.⁵

Sleep duration is an important dimension of sleep. Extremes of sleep duration appear to carry health risks and are quite common in the general population: in the United States, approximately 28% of adults sleep six hours or less, while over 8% sleep nine or more hours over a period of 24 hours.⁶ Despite the magnitude of these findings, epidemiological data evaluating the impact of sleep duration on immunity has been slow to come forward.

This issue of SLEEP includes a report of a large North American study by Patel and colleagues⁷ that explores the relationship between sleep duration and incident cases of pneumonia in a young cohort of female nurses free of risk factors for pneumonia, such as cancer, cardiovascular disease, diabetes, asthma, and prior history of pneumonia. Data regarding sleep duration were obtained cross-sectionally by self-report in 2001 as part of the Nurses' Health Study II cohort. Confirmed by chest x-ray and validated by a physician, the first documented episode of pneumonia occurring over the ensuing 4-year period (between 2001 and 2005) was the main outcome. Over 217,500 person-years of follow-up, 977 cases of pneumonia were identified. After adjusting for confounders, compared with a reference of eight hours sleep duration, sleeping less than five hours and sleeping more than nine hours were both associated with increased risk of pneumonia. This study brings forward groundbreaking epidemiological data from a large prospectively followed cohort of middle-aged women, strengthening the level of evidence that sleep does indeed influence immunity.

Exploring the relationship between sleep duration and risk of pneumonia at a population level is a novel undertaking and exposes further targets to improve the status of affected individuals. To date, few studies have addressed the relationship between sleep and the respiratory system response to infectious challenges. In a study of healthy volunteers exposed to nasal drops containing a rhinovirus, poorer sleep efficiency and shorter sleep duration predicted increased susceptibility to the development of a cold.⁸ Partial sleep deprivation in rats led to positive bacterial lung cultures as early as five days, suggesting that immunological vulnerability starts early during chronic sleep deprivation.⁹

While sleep deprivation studies provide some theoretical background for the relationship between short sleep duration and pneumonia, the novel association uncovered by Patel et al.⁷ between long sleep (nine or more hours/day) duration and increased incidence of pneumonia indicates that the relationship is not linear, and different mechanisms may be at play. This may resemble the relationship between sleep duration and mortality, where long sleep duration has been suggested to rather be a marker of suboptimal health, reflecting multiple comorbidities and low activity status¹⁰; nonetheless, this association needs to be further elucidated.

Many studies, including Patel et al., use questionnaires to assess sleep duration at a given point in time, introducing limitations in regard to differentiating time in bed as opposed to time asleep,¹⁰ changes in sleep duration over time, and proper alignment of sleep-wake cycle with circadian rhythms. The interaction between sleep and circadian factors in modulating immune responses is particularly intriguing. Circadian clocks appear to sustain certain rhythms of immune function. Most immune cells, with the exception of NK cells, were noted to have their peak pro-inflammatory activity at night.¹¹ By preferentially increasing the number of interleukin-12 producing monocytes, sleep induces a 24-hour oscillation between type 1 and 2 cytokines, which acts to globally increase the efficacy of adaptive immune responses.¹² Chronic sleep disruption may desynchronize circadian clocks and disregulate immune responses.¹¹

Corroborating findings by Patel et al.⁷ with the observation that even a relatively small amount of sleep loss influences risk of developing a respiratory infection⁸ leads us to suggest that further research is needed to find out the dose-response effect of sleep duration on risk of infections in general, and respiratory infections in particular. Objective means to phenotype habitual short and long sleepers, including ways to assess individual variability in regard to sleep duration and vulnerability to sleep deprivation will help us understand better these relationships.¹³ The effect of sleep recovery may also be explored and strategies could be developed for interventions at specific levels of sleep loss. The effects of shift work on immunity also need to be explored, particularly since shift work is associated with a higher prevalence of common cold, flu-like illness, and gastroenteritis compared to stable daytime work schedules.¹⁴ Last, but not least, it is paramount to determine whether studies of sleep deprived vaccinated animals who respond as though they have never been immunized¹⁵ are replicable at a population level in humans. We feel that public health policies will need to account for these findings, especially in the case of certain populations such as healthcare workers, who are much more likely to experience high rates of sleep duration extremes and for whom the success of immune response to infectious challenges (for example flu or emerging infectious diseases) is vital for their and their patients' well-being.

DISCLOSURE STATEMENT

The authors have indicated no financial conflicts of interest.

CITATION

Teodorescu MC; Teodorescu M. Tired and sick. SLEEP 2012;35(1):15-16.