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Poor-quality sleep and irregular sleep could be important drivers of breathlessness in patients who were previously hospitalized for COVID-19, according to data from the UK’s CircCOVID study.
The researchers, led by John Blaikley, MRCP, PhD, respiratory physician and clinical scientist from the University of Manchester, United Kingdom, found that sleep disturbance is a common problem after hospital admission for COVID-19 and may last for at least 1 year.
The study also showed that sleep disturbance after COVID hospitalization was associated with dyspnea and lower lung function. Further in-depth analysis revealed that the effects of sleep disturbance on dyspnea were partially mediated through both anxiety and muscle weakness; however, “This does not fully explain the association, suggesting other pathways are involved,” said Blaikley.
The study was jointly conducted by researchers from the University of Leicester, United Kingdom, as well as 20 other UK institutes and the University of Helsinki, in Finland. It was presented at this year’s European Congress of Clinical Microbiology & Infectious Diseases and was simultaneously published in The Lancet Respiratory Medicine.
“Sleep disturbance is a common problem after hospitalization for COVID-19 and is associated with several symptoms in the post-COVID syndrome,” said Blaikley. “Clinicians should be aware of this association in their post-COVID syndrome clinics.”
He added that further work needs to be done to define the mechanism and to see whether the links are causal. “However, if they are, then treating sleep disturbance could have beneficial effects beyond improving sleep quality,” he told Medscape Medical News in an interview.
Earlier this month, Medscape Medical News published a report on a large study that showed that 4 in 10 people with post-COVID syndrome had moderate to severe sleep problems. Black people were at least three times more likely than White people to experience sleep problems. A total of 59% of all participants with long COVID reported having normal sleep or mild sleep disturbances, and 41% reported having moderate to severe sleep disturbances.
Unlike prior studies that evaluated sleep quality after COVID-19, which used either objective or subjective measures of sleep disturbance, the current study used both. “Using both measures revealed previously poorly described associations between sleep disturbance, breathlessness, reduced lung function, anxiety, and muscle weakness,” Blaikley pointed out.
Subjective and Objective Measures of Sleep
The multicenter CircCOVID cohort study aimed to shed light on the prevalence and nature of sleep disturbance after patients are discharged from hospital for COVID-19 and to assess whether this was associated with dyspnea.
The study recruited a total of 2320 participants who were part of a larger parent PHOSP-COVID study. After attending an early follow-up visit (at a median of 5 months after discharge from 83 UK hospitals for COVID-19), 638 participants provided data for analysis as measured by the Pittsburgh Sleep Quality Index (a subjective measure of sleep quality); 729 participants provided data for analysis as measured by actigraphy (an objective, wrist-worn, device-based measure of sleep quality) at a median of 7 months.
Breathlessness, the primary outcome, was assessed using the Dyspnea-12 validated questionnaire.
Actigraphy measurements were compared to an age-matched, sex-matched, body mass index (BMI)–matched, and time from discharge–matched cohort from the UK Biobank (a prepandemic comparator longitudinal cohort of 502,540 individuals, one fifth of whom wore actigraphy devices). Sleep regularity was found to be 19% less in previously hospitalized patients with post-COVID syndrome, compared to matched controls who had been hospitalized for other reasons.
This “revealed that the actigraphy changes may be, in part, due to COVID-19 rather than hospitalization alone,” said Blaikley.
Data were collected at two time points after hospital discharge: 2–7 months (early), and 10–14 months (late). At the early time point, participants were clinically assessed with respect to anxiety, muscle function, and dyspnea, and lung function.
After discharge from hospital, the majority (62%) of post-COVID-19 participants reported poor sleep quality on the Pittsburgh Sleep Quality Index questionnaire. A “comparable” proportion (53%) felt that their quality of sleep had deteriorated following hospital discharge according to the numerical rating scale (subjective measure).
Also, sleep disturbance was found likely to persist for at least 12 months, since subjective sleep quality hardly changed between the early and late time points after hospital discharge.
Both subjective metrics (sleep quality and sleep quality deterioration after hospital discharge) and objective, device-based metrics (sleep regularity) were found to be associated with dyspnea and reduced lung function in patients with post-COVID syndrome.
“One of the striking findings in our study is the consistency with breathlessness and reduced lung function across different methods used to evaluate sleep,” highlighted Blaikley.
“The other striking finding was that participants following COVID-19 hospitalization actually slept longer [65 min; 95% CI, 59 – 71] than participants hospitalized for non-COVID; however, their bedtimes were irregular, and it was this irregularity that was associated with breathlessness,” he added.
In comparison to nonhospitalized controls, also from the UK Biobank, study participants with lower sleep regularity had higher Dyspnea-12 scores (unadjusted effect estimate, 4.38; 95%: CI, 2.10 – 6.65). Those with poor sleep quality overall also had higher Dyspnea-12 scores (unadjusted effect estimate, 3.94; 95% CI, 2.78 – 5.10), and those who reported sleep quality deterioration had higher Dyspnea-12 scores (unadjusted effect estimate, 3,00; 95% CI, 1.82 – 4.28).
In comparison to hospitalized controls, CircCOVID participants had lower sleep regularity index (-19%; 95% CI, -20 to -16) and lower sleep efficiency (3.83 percentage points; 95% CI, 3.40 – 4.26).
Sleep disturbance after COVID hospitalization was also associated with lower lung function, from -7% to -14% reduction in predicted forced vital capacity, depending on which sleep measure used.
In an analysis of mediating factors active in the relationship between sleep disturbance and dyspnea/decreased lung function, the researchers found that reduced muscle function and anxiety, which are both recognized causes of dyspnea, could partially contribute to the association.
Regarding anxiety, and depending on the sleep metric, anxiety mediated 18% to 39% of the effect of sleep disturbance on dyspnea, while muscle weakness mediated 27% to 41% of this effect, reported Blaikley. Those with poor sleep quality were more likely to have mild, moderate, or severe anxiety compared to participants who reported good-quality sleep.
A similar association was observed between anxiety and sleep quality deterioration.
“Two key questions are raised by our study: Do sleep interventions have a beneficial effect in post COVID 19 syndrome, and are the associations causal?,” said Blaikley. “We hope to do a sleep intervention trial to answer these questions to explore if this is an effective treatment for post COVID-19 syndrome.”
“Underlying Mechanisms Remain Unclear”
Amitava Banerjee, MD, professor of clinical data science and honorary consultant cardiologist, Institute of Health Informatics, UCL, welcomed the study but noted that it did not include nonhospitalized post-COVID patients.
“The majority of people with long COVID were not hospitalized for COVID, so the results may not be generalizable to this larger group,” she told Medscape Medical News. “Good-quality sleep is important for health and reduces risk of chronic diseases; quality of sleep is therefore likely to be important for those with long COVID in reducing their risk of chronic disease, but the role of sleep in the mechanism of long COVID needs further research.”
In a commentary also published in The Lancet Respiratory Medicine, W. Cameron McGuire, MD, pulmonary and critical care specialist from San Diego, California, and colleagues write, “These findings suggest that sleep disturbance, dyspnea, and anxiety are common after COVID-19 and are associated with one another, although the underlying mechanisms remain unclear.”
The commentators “applauded” the work overall but note that the findings represent correlation rather than causation. “It is unclear whether sleep disturbance is causing anxiety or whether anxiety is contributing to poor sleep…. For the sleep disturbances, increased BMI in the cohort reporting poor sleep compared with those reporting good sleep might suggest underlying obstructive sleep apnea…,” they write.
McGuire and colleagues add that many questions remain for researchers and clinicians, including “whether anxiety and dyspnoea are contributing to a low arousal threshold [disrupting sleep], …whether the observed abnormalities (eg, in dyspnea score) are clinically significant,” and “whether therapies such as glucocorticoids, anticoagulants, or previous vaccinations mitigate the observed abnormalities during COVID-19 recovery.”
Blaikley has received support to his institute from an MRC Transition Fellowship, Asthma + Lung UK, NIHR Manchester BRC, and UKRI; grants to his institution from the Small Business Research Initiative Home Spirometer and the National Institute of Academic Anaesthesia; and support from TEVA and Therakos for attending meetings. He is a committee member of the Royal Society of Medicine. A co-author received funding from the National Institutes of Health and income for medical education from Zoll, Livanova, Jazz, and Eli Lilly. Banerjee is the chief investigator of STIMULATE-ICP (an NIHR-funded study) and has received research funding from AstraZeneca.
2023 European Congress of Clinical Microbiology & Infectious Diseases: Presented April 17, 2023.
Lancet Respir Med. Published online April 15, 2023. Full text