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All across the globe, people’s lives, as well as their physical and mental well-being, have been affected by the COVID-19 pandemic. The stress and strain of home life, as well as being a healthcare professional in this time, and the wider societal impact of COVID-19 have led to altered sleep patterns in many people and specifically in healthcare professionals on the frontline in the fight against COVID-19. Sleep is important in helping to maintain overall occupational performance and overall well-being. It is also vital to have an understanding of the importance of sleep and the immune response during these times. Sleep may very well be one of the most important prophylactics to keep people's physical and mental state healthy during the pandemic.[1]
Sleep Stages
There are two major phases of sleep:
Non-rapid eye movement (NREM) sleep
Rapid eye movement (REM) sleep
Non-rapid eye movement (NREM) sleep is subdivided into three stages (N1, N2 and N3) of increasing sleep depth.
Non-rapid eye movement (NREM) sleep Stage 1 (N1)
the transition period from being awake to being asleep
noises and activity in the surrounding environment may fail to generate a response
the transitional period between light sleep and very deep sleep
REM sleep
the brain becomes more active
the body becomes relaxed and immobilised
dreams occur
eyes move rapidly
Sleep occurs once during a 24-hour circadian rhythm. During this sleep period, wakefulness progresses cyclically to NREM sleep and then to REM sleep. There are short periods of arousal or awakening after a REM sleep period. The cycle of NREM to REM sleep lasts for about 80 - 110 minutes over the course of the night. Typically humans will have four to six of these cycles in a sleep period.[2]
Screen time later in the evening has a negative impact on sleep as it stimulates the brain and keeps it from winding down. The blue light from screens suppresses the production of melatonin.
For healthcare professionals sleep is a public health and safety issue. Poor sleep has been linked to mental health issues, physical health issues and is related to stress and anxiety.[6] It is also an occupational health hazard in the context of healthcare where so many healthcare professionals are already in a fatigued state and overworked during the COVID-19 pandemic.[1]
Immunology and Sleep
There is a bidirectional link between sleep and the immune system.
Sleep is altered by immune system activation and the innate and adaptive immune systems are affected by sleep.
Depending on the magnitude and time of an inflammatory response stimulated by the immune system, sleep can be increased in duration and intensity but also disrupted.
An infection makes us tired and increases the desire to sleep and sleep is often recommended as being “the best medicine.”
It has also been shown that prolonged sleep loss weakens the body’s immune system and renders it prone to colds or other infections. There is strong evidence that sleep enhances immune function and helps the body to heal.[7]
Neuroimmune Interactions
The communication between sleep regulatory networks in the central nervous system and the cells and tissues of the immune system is bidirectional. Sleep is important for the proper functioning of the immune system. In order to understand the relationship between the nervous system and the immune system, there are certain neuroimmune interactions based on specific anatomical and physiological conditions:[8]
Neurons and immune cells share similar intercellular signals such as hormones, neurotransmitters and modulators, cytokines and chemokines
Some of these shared signals can cross the blood-brain barrier in both directions
Immune cells traffic to all sites in the body and they come into close contact to nerve endings and the brain
Lymphatic tissues (both primary (thymus and bone marrow) as well as secondary (spleen, lymph nodes)) are innervated by sympathetic and partly by sensory nerves
Endocrine and autonomous nervous systems regulate immune function directly via hormones and neural intervention as well as indirectly through influences on blood flow, blood pressure and lymph flow
These conceptual borders between hormones, neurotransmitters, cytokines and chemokines are blurred and multi-functional (e.g. norepinephrine is a hormone released from the adrenal glands and a neurotransmitter in the central nervous system).[8]
Key players in the Immune System
Leukocytes (white blood cells) are the cellular key players in the immune system. Leukocytes can be differentiated according to their:
development as part of the innate or adaptive immune system
site of maturation (thymus - T cells; bone marrow - B cells)
site of the primary action
antigen specificity
function
cytokine profile
These cells serve immune defence and are responsible for the detection and elimination of molecules and cells bearing foreign antigens and/or altered self-antigens. This indicates in a broader sense, cellular damage and therefore danger.[7][8] (In the COVID-19 pandemic this antigen may be SARS-CoV-2)
Adaptive Immune Response to Infection
The most important steps of an adaptive immune response to infection are[7][8]:
The invading antigen is taken up by cells such as macrophages, dendritic cells (DC) or B cells, These cells are attracted to the intrusion site by “danger signals” (these are signals released locally due to tissue injury).
These cells then migrate to the draining lymph node via afferent lymphatics.
The antigen is then presented to Th cells with the respective T cell receptor to form the “immunological synapse.”
The cells become activated and they proliferate and differentiate into Th1 or Th2 cells.
Thereby a progeny of thousands of antigen-specific Th cells is produced.
These Th cells help the B-cells to become antibody-producing plasma cells and leave the lymph node after several days to support macrophages in eliminating the pathogen (SARS-CoV-2 in COVID-19).
Some of these antigen-specific cells survive and these cells represent the immunological memory which aids in a faster and more effective immune response if the antigen is ever re-encountered.
Pro-inflammatory State during Sleep
During the nocturnal sleep period in humans, the two main stress systems are down-regulated. These systems are the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system(SNS). Alongside this down-regulation, there is a drop in blood levels of cortisol, epinephrine and norepinephrine. In contrast to this, mediators such as the pituitary growth hormone (GH), prolactin and melatonin show an increase in blood levels during sleep. These mediators serve cell growth, differentiation and restoration.[8]
Sleep is a pro-inflammatory process. Growth hormone, prolactin and melatonin are pro-inflammatory signals that support immune cell activation, proliferation, differentiation and the production of pro-inflammatory cytokines such interleukin, IL-12, tumour necrosis factor (TNF)-alpha and of Th1 cytokines like interferon (IFN). In contrast to this, these type of immune functions is generally suppressed by cortisol and catecholamines (which are suppressed during sleep) in an anti-inflammatory way. Considering this, research has shown a pattern of endocrine and immune rhythms reflecting an “inflammatory peak” during nocturnal sleep. Wakefulness is associated with prevalent anti-inflammatory activity.[8]
These peaks of pro-inflammatory cytokines during the rest period are often reported during the early slow-wave sleep (SWS) dominated part of sleep. The benefits of this pro-inflammatory function of sleep can be seen in response to vaccinations. Sleep after vaccinations can enhance the adaptive immune response against the invading antigen. In a study with participants who received a hepatitis A vaccination, it has been shown that the participants who slept regularly on the first night after the vaccination, showed a two-fold increase in antigen-specific antibodies compared to the group of participants who stayed awake the first night after the vaccination. Furthermore, these immune-enhancing effects of sleep were still evident at a 1-year follow-up. This supports the hypothesis that sleep not only enhances the initial formation of an adaptive immune response but also aids in the long-term maintenance of the antigenic memory.[9]
Strong evidence exists to support the notions that the processes of immune activation and proliferation involving pro-inflammatory cytokines are timed to the nocturnal resting period. However, there is no clear reason for this. It should be considered though that inflammation present in a wakeful state causes malaise, fatigue, immobility, pain and several aspects of illness. These aspects of inflammation are incompatible with the demands of mental and physical activity required during the day or with one's specific environmental challenges. Confining these aspects to sleep periods, therefore, seems appropriate.[8]
Immune activation, like protein synthesis and cell proliferation, is an energy-dependent process. Endocrine changes during sleep permit the allocation of energy-rich fuels like glucose from insulin-dependent tissue such as muscle, to the immune system. Oxidative stress is caused by inflammation and this as well as cell injury is counteracted by melatonin (a hormone that is only secreted during night time). These may be some reasons for initiating the adaptive immune responses during the sleep period.[7][8]
Contracting a virus or having a pathogen encounter will most likely occur in a wakeful or active state. (eg. a healthcare provider working in a hospital). Our body’s immune response kicks in quickly when we contract a virus and wards off any challenges in the peripheral tissues, but we need sleep for the slower-long term processes of adaptive immunity development in the lymph nodes as well as in the long term prevention of illness having a prolonged impact.[8]
Prolonged periods of sleep loss can lead to negative changes in health and immune function. In studies investigating the effects of prolonged sleep deprivation, a general enhancement in markers for inflammatory activity was reported. Eighty-eight hours of sleep deprivation or 10 days of sleep restriction to 4 hours per night increased the concentration of C-reactive protein, a biomarker of inflammation.[11] Even mild restrictions of sleep have been shown to increase the level of pro-inflammatory cytokines.
Although both sleep and sleep deprivation leads to an increase in pro-inflammatory activity, it has been suggested that the enhanced pro-inflammatory activity during sleep specifically supports cytokine production needed for adaptive immune responses, whereas during sleep deprivation it seems unspecific. The low-grade systemic inflammation associated with sleep deprivation is also associated with medical conditions such as diabetes type 2, cardiovascular disease and obesity.[7]
Prolonged sleep loss or chronic sleep loss is also associated with immunodeficiency. Research has shown a weakened immune response to the influenza vaccination after 6 days of restricted sleep.[12] There is also evidence for enhanced susceptibility to the common cold associated with chronic sleep loss.
Chronic sleep deprivation can be considered as an unspecific state of chronic stress, which does impact immune function and general health.
Sleep and Healthcare Professionals
During this pandemic healthcare professionals are in the frontline and delivering incredible service. Alongside these healthcare professionals are the scientists and public health leaders who are working to find the best forms of treatment as well as creating strategies to prevent the spread of the virus. This scenario inevitably leads to fatigue, stress and unfortunately sleep deprivation.[13]
This lack of sleep or sleep debt suppresses the body’s immune response and disrupts circadian rhythms. At the moment there is no research that links an increased diagnosis of COVID-19 with sleep debt, but the suppressed immune response may increase the risk of developing the disease and the worsening of the clinical condition caused by COVID-19. Research on the adverse effects on the mental health of frontline healthcare professionals during COVID-19 has shown that insomnia is the most commonly reported symptom.[14] Sleep plays such a key role in emotion regulation and body homeostasis and the disturbance of it can have detrimental consequences. Patient safety and healthcare professional well-being are closely linked and it is therefore paramount to ensure good sleep health. Healthcare professionals involved in the direct care of patients with COVID-19 had a high risk for insomnia, depression, anxiety and distress. These symptoms were more prevalent in nurses, females and in areas with high case infection rates.[14]
The following factors specifically play a combined role in the sleep of healthcare professionals[14]:
Personal safety concerns
Transmitting the disease to family members
Stigmatization from being infected
Shift work
Interpersonal isolation
Furthermore, lifestyle modifications such as stay at home policies and self-isolation can cause sleep disturbances. Other factors that could have a negative impact on sleep health in healthcare professionals during COVID-19 is the redeployment to areas outside of a healthcare professionals normal scope of practice.[14]
Sleep Hygiene Recommendations
Healthcare professionals should prioritise sleep and practice good sleep hygiene. Ways to do this include[13]:
Keep a consistent sleep schedule
Get at least 7 hours of sleep
Do not go to bed unless sleepy
Establish a relaxing bedtime routine
Keep the bedroom quiet
Keep the bedroom at a comfortable temperature
Turn off electronic devices at least 30 min before bedtime
Do not eat a large meal before bedtime
Physical activity/exercise
Avoid consuming caffeine in the late afternoon or evening - or have a caffeine intake cut-off time
Avoid consuming alcohol before bedtime
Ensure adequate exposure to natural light
Nap for no longer than 30 minutes
It is evident that people with a weakened immune system are at greater risk of contracting the coronavirus and have greater difficulty in effectively fighting the virus once contracted. Frontline healthcare professionals are in regular and close contact with patients with COVID-19 on a daily basis. It is therefore paramount that health care professionals optimise their well-being to reduce the risk of contracting and transmitting the virus. PPE and professional modifications help with this, but alongside this healthcare professionals need to make personal adaptations in their own lives to improve their resilience. Stress management is also important in the context of COVID-19.[1]
Interventions for Optimal Sleep Health
If you are struggling to sleep (many healthcare professionals are!) for reasons such as anxiety related to work it may be useful to consider practising behavioural therapy programmes - have been shown to be effective in addressing insomnia related to anxiety. This type of therapy includes cognitive behavioural therapy and acceptance and commitment therapy. Various options are available and a consultation with a sleep physician or psychologist to determine the best option.[14]
Sleep medications, such as hypnotic medications and over the counter prescription sleeping pills, should be avoided as much as possible. Consider the risks and benefits of taking these medications and it is best to seek medical advice of a sleep physician wherever necessary.
Underlying the principles of behavioural therapies is the concept of mindful practice and a mindful state. Mindfulness is defined as a state of practice which validates and accepts and approaches thoughts and emotions and behaviours in a non-judgmental but inquisitive manner. Healthcare professionals should be mindful of their emotional and mental health. Mindfulness reduces sympathetic nervous activation which keeps us alert and encourages parasympathetic nervous system activation which allows us to translate into a state of slumber.[1]
Healthcare professionals are often involved in shift work and this can impair sleep and daytime functioning. Ways to deal with shift work can include[14]:
Giving more priority to sleep
Trying to stay alert during the night shift
Prevention of excessive daytime sleepiness or accidents if excessively sleepy
Conclusion
The effects of COVID-19, such as the prevalence of the virus in hospital settings as well as an increased workload, are likely to be present for quite some time still. Prioritising sleep and your well-being and combining this with good practices of nutrition, physical activity and mental health care will be important to prevent burnout and fatigue and the risk of the more negative effects associated with contracting the virus.
References
↑ 1.01.11.21.3Whelehan, D. COVID-19 and Sleep. Course, Plus2020.
↑Irwin MR. Sleep and inflammation: partners in sickness and in health. Nature Reviews Immunology. 2019 Nov;19(11):702-15.
↑Mattress Clarity. What Are Sleep Cycles? - Everything You Need To Know! Published on 9 October 2019. Available from https://www.youtube.com/watch?v=9ut6UOTRdBw. (last accessed 04 June 2020)
↑Belingheri M, Paladino ME, Riva MA. Working schedule, sleep quality and susceptibility to COVID-19 in healthcare workers [published online ahead of print, 2020 Apr 27]. Clin Infect Dis. 2020;ciaa499.
↑Lange T, Perras B, Fehm HL, Born J. Sleep enhances the human antibody response to hepatitis A vaccination. Psychosomatic medicine. 2003 Sep 1;65(5):831-5.
↑Lifestyle facts.Strengthen Your Immune System with Sleep. Published on 11 February 2018. Available from https://www.youtube.com/watch?v=GDT16SxG0Cc (last accessed 4 June 2020)
↑Meier-Ewert HK, Ridker PM, Rifai N, Regan MM, Price NJ, Dinges DF, Mullington JM. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. Journal of the American College of Cardiology. 2004 Feb 18;43(4):678-83.
↑Spiegel K, Sheridan JF, Van Cauter E. Effect of sleep deprivation on response to immunizaton. Jama. 2002 Sep 25;288(12):1471-2.
