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Sleep and the Covid-19 Pandemic

Summary:
“Sleep that knits up the ravell’d sleave of care” –William Shakespeare By Lambert Strether of Corrente For many months I’ve been able to recall my dreams on waking, which is new for me. I remembered that strange dreams were in the second tier of some symptoms lists circulated[1] for the original Wuhan, pre-Alpha strain of Covid-19, and it crossed my mind — though not concernedly enough for me to get a test to see if I am seropositive — that at some point I’d had an asymptomatic case (infection anecdotes; post-vaccination anecdotes). It then occurred to me that we’ve never run a post on Covid and sleep, so here we are. Through a natural association, I had “sleep” filed along with “sex” and “death” as things we don’t understand, recalling Michael Brook’s book, 13 Things That Don’t Make

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“Sleep that knits up the ravell’d sleave of care” –William Shakespeare

By Lambert Strether of Corrente

For many months I’ve been able to recall my dreams on waking, which is new for me. I remembered that strange dreams were in the second tier of some symptoms lists circulated[1] for the original Wuhan, pre-Alpha strain of Covid-19, and it crossed my mind — though not concernedly enough for me to get a test to see if I am seropositive — that at some point I’d had an asymptomatic case (infection anecdotes; post-vaccination anecdotes). It then occurred to me that we’ve never run a post on Covid and sleep, so here we are.

Through a natural association, I had “sleep” filed along with “sex” and “death” as things we don’t understand, recalling Michael Brook’s book, 13 Things That Don’t Make Sense, which has them each as one of those things. Brooks did not, in fact, include sleep, but he might as well have. From Neuroscience in 2001:

Sleep (or at least a physiological period of quiescence) is a highly conserved behavior that occurs in animals ranging from fruit flies to humans. This prevalence not withstanding, why we sleep is not well understood.

And from the Sleep Foundation, twenty years later:

Even after decades of research, the exact reason why we sleep remains one of the most enduring and intriguing mysteries in health science.

As a sidebar, the fact that we don’t understand many of the most important things in life might lead one to question the universality of the meritocratic ideal, given that advancement within a meritocracy is driven by what can be known, not by what is not known, or not knowable. End sidebar.

We do know that being deprived of sleep is bad. From the American Psychological Association:

Decades of research have linked chronic sleep deprivation to an increased risk for obesity, heart disease, Type 2 diabetes, and problems with immune function (“Sleep and Sleep Disorders,” Centers for Disease Control and Prevention). Sleeping more or less than recommended—typically 7 to 9 hours a night—is a significant predictor of death by any cause (Cappuccio, F. P., et al., Sleep, Vol. 33, No. 5, 2010). Sleep disturbances also hinder social, motor, and cognitive skills and predict suicide risk, depression, and other mental health problems (Bernert, R. A., et al., Current Psychiatry Reports, Vol. 17, 2015; Fang, Y., et al., npj Digital Medicine, Vol. 4, 2021; “Mental health and sleep,” Sleep Foundation).

We also know that much of the world had been deprived of sleep, before the current Covid-19 pandemic. From Sleep:

There is growing evidence, mostly from populations in Western countries, pointing to downward trends in the average duration of sleep and increasingly higher prevalence of insomnia and other sleep disturbances. For example, data from nationwide surveys in Canada and the United States indicate that more than 20% of the general adult population suffer from insomnia, and this number is likely to increase over the next few decades. These percentages are consistent with prevalence figures of short sleep duration reported in population-based studies across different Western countries over the past 3 decades. More broadly, problems with falling asleep or day-time sleepiness and fatigue affect even larger segments of the population, imposing a considerable burden in terms of morbid-ity and mortality outcomes, as well as substantial cost implica-tions for society in developed settings.

And that’s Western countries. In this study:

To our knowledge, this is the first report on sleep problems and associated factors in a large number of older adults across 8 populations from low-income settings in Africa and Asia. Overall, 16.6% of adults age 50 yr and older reported sleep problems in this study.

So, at least in the instance of sleep, there is no “normal” to return to; we should not assume that we’ll all get “a good night’s sleep” once Covid has been eradicated reduced to the status of a lethal disease that’s not part of the narrative.

With that, I will turn to Covid-19 and sleep. This post has no thesis. Rather, I’ve gathered a good deal of intriguing material, though not systematically enough to call this post a survey (the two fields of sleep of Covid are both huge). I hope the material has educational value in itself; it may also inform your practice in daily life. I’ve sorted the material into two buckets: The effect of SARS-COV-2, the virus, on sleeping individuals; and the effect of COVID-19, the disease, on populations. Naturally, I am not offering medical advice (or dosages, or anything like that).

SARS-COV-2 and the Sleeping Individual

Here, I will look at sleep and vaccine efficacy, circadian rhythms, and melatonin. Interestingly, the last two may involve repurposing drugs (always a plus, in my book).

Vaccine Efficacy

From The Lancet, “Could a good night’s sleep improve COVID-19 vaccine efficacy?”:

Although data from phase 3 trials indicate that factors such as age and biological sex might not be as prominent in modulating the efficacy of certain COVID-19 vaccines (eg, in case of the mRNA-based COVID-19 vaccine produced by Pfizer and BioNTech),2 the role of sleep in this context is unclear. As suggested by previous studies, sleep duration at the time of vaccination against viral infections can affect the immune response. For instance, 10 days after vaccination against the seasonal influenza virus (1996–97), IgG antibody titres in individuals who were immunised after four consecutive nights of sleep restricted to 4 h were less than half of those measured in individuals without such sleep deficits. Similarly, shorter actigraphy-based sleep duration was associated with a lower secondary antibody response to hepatitis B vaccination. Sleep might also boost aspects of virus-specific adaptive cellular immunity. Compared to wakefulness, sleep in the night following vaccination against hepatitis A doubled the relative proportion of virus-specific T helper cells, which are known to play a prominent role in host-protective immune responses. Interestingly, in individuals who slept the night after the first vaccination, the increase in the fraction of interferon-γ (IFN-γ)-positive immune cells at weeks 0–8 was significantly more pronounced than in those who had stayed awake on that night.

So, if your answer to the Lancet’s question is “Yes,” at the very least, sleep is an enormous confounder for all the vaccine studies, which is pretty funny when you think about it.

Circadian Rhythms

Circadian rhythms are the body’s cron jobs: They cycle through essential functions and processes. One such is the sleep-wake cycle. From the European Respiratory Journal, “Putative contributions of circadian clock and sleep in the context of SARS-CoV-2 infection

Sleep, a circadian behavioral manifestation of major regulatory homeostatic mechanisms such as those associated with immunity, has also been shown to interact with host defenses at the molecular and cellular levels. Indeed, extensive literature has indicated the important role of homeostatic sleep in innate and adaptive immunity [46]. Furthermore, there are clear reciprocal dependencies between sleep duration and quality and the immune responses against viral, bacterial, and parasitic pathogens, the latter altering in turn sleep patterns [46]. Thus, it is likely that improved sleep quality and duration in the population may mitigate the propagation and severity of disease induced by SASRS-Cov-2 infection.

It doesn’t really seem that sleep duration and quality are optimal in a hospital setting. That said, qualifications along with speculative mechanisms:

As mentioned above, it is unclear how disrupted or insufficient sleep may affect SARS-Cov2 infection rates and the severity of its clinical manifestations. Typical symptoms of acute lung injury (ALI) include dyspnea, hypoxemia and pulmonary edema which may deteriorate into the severe acute respiratory syndrome (SARS). The cell-based pathological mechanisms of such progression involve activation of immune-inflammatory cascades resulting in disruption of the alveolar- apillary barrier. This immuno-inflammatory activation is influenced by the circadian clock, and therefore deregulation of circadian rhythms such as in night shift workers or social jetlag could play a disease-specific role by altering the susceptibility to infection or modifying the clinical manifestations of COVID-19 syndrome…. Furthermore, since ACE2, which may be regulated by clock activity, was shown to have a protective effect through suppression of apoptosis of pulmonary endothelial cells, it is possible that chronobiological interventions may mitigate the progression of lung injury, if such interventions occur in a very early stage of the infection.

At the very least, it does seem sensible to think about incorporating circadian rhythms when administering drugs. From Frontiers in Neuroscience, “COVID-19: Sleep, Circadian Rhythms and Immunity – Repurposing Drugs and Chronotherapeutics for SARS-CoV-2″:

Evidence from the literature suggests that nearly half of all physiological functions, including the body’s pathogenic response, are controlled tightly by the circadian clock. Chronotherapy exploits this rhythmic pattern to its advantage to improve the outcome of different medical interventions as discussed throughout this review. This manuscript highlights that diurnal variation exists in the functioning of our immune system, in vivo cholesterol synthesis, coagulation, fibrinolysis and blood pressure, and that considering the time of drug administration might significantly improve the treatment and management of the novel coronavirus disease-19.

The drugs discussed for repurposing include statins, blood thinners/anticoagulants, and antihypertensive drugs. The piece also references melatonin, to which we now turn.

Melatonin

Melatonin is a hormone that induces sleep in humans; the brain produces it in response to darkness. (“Research suggests that melatonin plays other important roles in the body beyond sleep. However, these effects are not fully understood.”) Media interest in melatonin as a Covid treatment seems to have peaked in 2020. That said, there’s continuing investigation of repurposing it (and of course it can also help put patients to sleep, as shown in this RCT). Here is a case for melatonin, from (Elsevier, peer-reviewed) Endocrine Practice, “Melatonin for the Early Treatment of COVID-19: A Narrative Review of Current Evidence and Possible Efficacy,” in August 2021. This is a meta-study. From the Results section:

The results showed that melatonin acts to reduce reactive oxygen species–mediated damage, cytokine-induced inflammation, and lymphopenia in viral diseases similar to COVID-19.

Here are a number of speculative mechanisms (details and pathways omitted):

Viral infection with SARS-CoV-2 can cause severe inflammatory responses and oxidative stress; the use of melatonin may be able to attenuate some of these reactions…. It is thought that SARS-CoV-2 causes severe lung pathology by inducing pyroptosis, which is a highly inflammatory form of programmed cell death…. Melatonin acts as an inhibitor of the NLRP3 inflammasome, inhibiting pyroptosis and ultimately exerting an anti-inflammatory effect… SARS-CoV-2 infection involves induction of a “cytokine storm”… Melatonin exerts anti-inflammatory effects through the reduction of proinflammatory cytokines… Furthermore, once inside the cell, SARS-CoV-2 begins its damaging oxidative effects starting with the recognition of its pathogen-associated molecular patterns by pattern recognition receptors located on host mitochondria and subsequent interaction with mitochondrial antiviral-signaling protein to initiate antiviral cascades resulting in excessive ROS production… Melatonin has been shown to reduce acute lung oxidative injury by suppression of ROS.

And much more:

Given the information presented here, melatonin has plausible benefits of reducing inflammation and possibly curbing the cytokine storm caused by SARS-CoV-2. Melatonin recommended early in the course of infection could provide benefit at a relatively low cost and a tolerable safety profile.

Currently, there are no published results from a clinical trial using melatonin as a treatment for COVID-19; however, our search provided 2 protocols for double-blind, randomized clinical trials utilizing melatonin dosages of 5 mg twice a day by oral capsule for 7 days and 5 mg per kg of bodyweight intravenously every 6 hours for 7 days. In addition, the clinicaltrials.gov website currently lists 6 ongoing studies (NCT04474483, NCT04784754, NCT04409522, NCT04530539, NCT04353128, and NCT04470297) using melatonin as treatment in patients with COVID-19 in both the intensive care unit and outpatient departments. Although these studies will provide insight into the effectiveness of melatonin in COVID-19, they do not focus on starting treatment as early as the day of diagnosis. In addition, an argument has been made that the treatment of COVID-19 with melatonin can be used before clinical trials…

Melatonin is available over the counter with indications for jet lag, nicotine withdrawal, winter depression, tardive dyskinesia, chemotherapy-related thrombocytopenia, and insomnia. The side effect profile remains relatively benign… Administration for preterm infants, children, and adolescents in various diseases has shown no side effect except at high doses. Caution should be exercised in patients on multiple medications due to potential unknown interactions and in patients taking a medication that can inhibit cytochrome P450, since melatonin is mainly metabolized by this enzyme.

Those who are at highest risk for developing severe cases of COVID-19 should receive treatment as quickly as possible. The current study argues that melatonin would be a cheap, safe, and effective first-line treatment for COVID-19, especially in higher-risk populations.

Melatonin is at least worth a look (and if you know anybody who’s looking, make sure they read the text following “relatively benign”, because I had to omit detail to save space. And read the whole thing, all the way to the end).

And now from individuals, let’s turn to populations.

COVID-19 and Sleeping Populations

The Covid-19 pandemic has had massive effects on sleep patterns all over the world. From Sleep Health, “Sleeping when the world locks down: Correlates of sleep health during the COVID-19 pandemic across 59 countries“:

The outbreak of COVID-19 in December 2019 rapidly escalated into a global pandemic affecting countries around the world, which imposed social isolation measures to stop the spread of the disease. The mass (home) confinement in addition to the uncertainty of the pandemic led to drastic changes in people’s lives, affecting social interaction, work, school, physical activity, and sleep.

Thus, the COVID-19 pandemic has imposed extreme psychological stress on many individuals, the extent of which we are only just beginning to understand.More than half the sample [n=6882, online survey distributed between April 19 and May 3, 2020 ] shifted their sleep toward later bed- and wake-times, and more than a third reported increased sleep disturbances during the pandemic. Older age, being partnered, and living in a higher income country were associated with better sleep health, while a stricter level of quarantine and pandemic-related factors (being laid off from job, financial strain, or difficulties transitioning to working from home) were associated with poorer sleep health. Domestic conflict was the strongest correlate of poorer sleep health. Poorer sleep health was strongly associated with greater depression and anxiety symptoms. Participants from Latin America reported the lowest sleep health scores.

Interestingly, changes in sleep patterns differ by country:

Sleep and the Covid-19 Pandemic

Covid and Dreams

Perhaps I’m not the only one. From Nature and Science of Sleep, “How our Dreams Changed During the COVID-19 Pandemic: Effects and Correlates of Dream Recall Frequency – a Multinational Study on 19,355 Adults“:

Many have reported odd dreams during the pandemic.

And:

To date, only a handful of studies have investigated how the pandemic is reflected in our dreams. Previous research indicates that experiencing collective threatening situations, such as earthquakes, hurricanes, and terrorist attacks, is associated with changes in dreams and sleep patterns. This would make sense as such experiences can cause immense psychological stress, and dreaming is hypothesized to be involved in emotional processing and emotional memory consolidation.

The study focused on Dream Recall Frequency (DRF), presumably because that can be measured:

We found that there was a significant increase in DRF during the pandemic, with 9.2% reporting heightened DRF, which is in line with other reports. Participants with high DRF during the pandemic experienced more pronounced changes in sleep behavior as a consequence of the pandemic, such as worsened sleep quality and more sleep problems.

….[T[here were no differences concerning DRF between people who reported having had COVID-19 and people who had not been infected.

But I wanted to know what the dreams were about! Imagine doing a study where your subject recalled a dream, then ticking a box and not finding out what the dream was. Anyhow, here, here, and here are some anecdotal reports, all of which include swarming behavior, which is pretty darn on the nose for zeitgeist, if you ask me.

Covid and Insomnia

From Vox, “The pandemic has created a nation of insomniacs.” Americans weren’t getting a good night’s sleep to begin with, but:

In one study conducted across 49 countries in March and April 2020, 40 percent of people said their sleep was worse than before the pandemic. Participants’ use of sleeping pills increased by 20 percent. Google searches for “insomnia” also spiked in the US in April and May, when many parts of the country were under stay-at-home orders. Meanwhile, Americans’ spending on the over-the-counter sleep supplement melatonin increased by 42.6 percent [see above] in 2020. “That consumer behavior is a sign that people are struggling,” [Jennifer Martin, a clinical psychologist who serves on the board of directors for the American Academy of Sleep Medicine] said.

Then there are the hundreds of thousands of people who have contracted Covid-19. While insomnia isn’t technically considered a symptom of the disease, the respiratory symptoms can make it difficult to sleep. And clinicians are seeing a lot of chronic sleep problems in people experiencing long Covid. “We’re still trying to learn about that, and whether it might play a role in making the recovery more difficult,” Martin said.

While there’s not yet much data on sleep trends this year, experts say the sleep disturbances of the early pandemic could persist over time. For one thing, plenty of people are still dealing with a lot of anxiety around the pandemic, from those who have lost their jobs to those dealing with the stress of sending kids to school amid the delta variant. As [Lauren Hale, a professor of family, population, and preventive medicine at Stony Brook University] put it, “everybody has their own reasons why they aren’t sleeping as well during an international crisis.”

For another, any stressful experience that disrupts sleep for a period of time risks triggering chronic insomnia. When patients are asked how their sleep problems started, they’ll typically mention some “stressful event or a big change in their life as a thing that sort of got them off track,” Martin said. “Short-term insomnia is how long-term insomnia starts.” That’s one reason some Americans may still be having trouble sleeping now, more than 18 months into the pandemic, even if they’re vaccinated and their personal fears around Covid-19 have (somewhat) abated.

Of course, we can’t have the labor force interfered with that way, so we’ve invented a new buzzword: “coronasomnia.” From the BBC:

[T]he ongoing coronavirus crisis has made getting a good night’s rest significantly harder. Some experts even have a term for it: ‘coronasomnia’ or ‘Covid-somnia’.

This is the phenomenon that’s hit people all over the world as they experience insomnia linked to the stress of life during Covid-19. In the UK, an August 2020 study from the University of Southampton showed that the number of people experiencing insomnia rose from one in six to one in four, with more sleep problems in communities including mothers, essential workers and BAME groups. In China, insomnia rates rose from 14.6% to 20% during peak lockdown. An “alarming prevalence” of clinical insomnia was observed in Italy, and in Greece, nearly 40% of respondents in a May study were shown to have insomnia.

Simple, more of us are now insomniacs. With the pandemic into its second year, months of social distancing have rocked our daily routines, erased work-life boundaries and brought ongoing uncertainty into our lives – with disastrous consequences for sleep. Our health and productivity could face serious problems because of it. Yet the scale of the problem could potentially bring change, introducing new elements into how we treat sleep disorders – and get our lives back on track.

“Get our lives back on track…” How cheery. As if the old normal was all that great. Whose track? Going where? But slipping into “News You Can Use” mode, here are some tips on dealing with insomnia.

Conclusion

So that’s what I found out about Covid-19 and sleep. I’m sure there’s much more to learn. But it does occur to me that a sleep-deprived population with bad dreams that they’re remembering for the first time might be unusually cranky in the aggregate, even more than their material circumstances might dictate, and that this might be one factor behind the decrease in (dread word) civility that many have commented upon. Getting no sleep is bad.

NOTES

[1] No, I can’t find where we linked to this, which we did, because wherever you turn search doesn’t work anymore.

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