key: cord-0709952-nwegekp0
authors: Del Brutto, Oscar H; Mera, Robertino M; Costa, Aldo F; Recalde, Bettsy Y; Castillo, Pablo R
title: Sleep quality deterioration in middle-aged and older adults living in a rural Ecuadorian village severely struck by the SARS-CoV-2 pandemic. A population-based longitudinal prospective study
date: 2021-02-20
journal: Sleep
DOI: 10.1093/sleep/zsab041
sha: fbeb90d092af814c6d13850a7809e682dd0be822
doc_id: 709952
cord_uid: nwegekp0

STUDY OBJECTIVES: This study assessed changes in sleep quality before and after the peak of the SARS-CoV-2 pandemic in community-dwellers enrolled in the Atahualpa Project. METHODS: Atahualpa residents aged ≥40 were eligible if they had a Pittsburgh Sleep Quality Index (PSQI) nine months before the pandemic and a lateral flow-based test for identification of SARS-CoV-2 antibodies during the peak of the pandemic. Six months later, individuals completed a follow-up PSQI. The independent relationship between SARS-CoV-2 infection and deterioration in sleep quality was assessed by fitting logistic mixed models for longitudinal data. RESULTS: Of 639 participants (mean age at baseline: 59±12.8 years), 325 (51%) had SARS-CoV-2 antibodies. A total of 185 (29%) individuals at baseline and 311 (49%) at follow-up were poor sleepers (p<0.001). Mixed logistic regression models demonstrated a significant increase in poor sleepers at follow-up (OR: 2.85; 95% C.I.: 2.16 – 3.75), which was more marked among SARS-CoV-2 seropositive subjects (OR: 3.8; 95% C.I.: 2.48 – 5.81). The adjusted proportion of poor sleepers increased from 29% to 56.2% (95% C.I.: 50.9 – 61.6%) among SARS-CoV-2 seropositive individuals, but only to 40.7% (95% C.I.: 35.3 – 46.1%) in their seronegative counterparts (p<0.001). Likewise, progression from a good to a poor sleeper status was higher among seropositive individuals than in their seronegative counterparts (38.1% versus 22.3%; p<0.001), after adjusting for relevant covariates. CONCLUSIONS: This study shows a deleterious effect of SARS-CoV-2 in sleep quality. An effect of SARS-CoV-2 in disrupting sleep-related pathways cannot be ruled out.

The SARS-CoV-2 pandemic has been associated with the occurrence of sleep-related disorders, not only in subjects affected by the virus but in the population at large [1] [2] [3] .

Lockdowns, loss of social and support networks, unemployment and fear to acquire this infection or to develop permanent sequelae, range top among psychological consequences of this pandemic. All these factors may contribute to a detriment in sleep quality, as suggested by the literature [4] [5] [6] [7] [8] [9] . However, most information came from studies using unstructured questionnaires applied online or through phone interviews, asking people about sleep problems during the lockdown or in patients evaluated at specialized clinics. A meta-analysis of published data on sleep disorders in COVID-19 patients up to August, 2020, disclosed that only a few studies used validated questionnaires, such as the Pittsburgh Sleep Quality Index (PSQI), yielding a pooled prevalence of poor sleep quality that ranged from 19% and 43% [10] . None of the studies included in that meta-analysis assessed the demonstration of changes (deterioration) of sleep quality before and after the start of the SARS-CoV-2 pandemic in both infected and non-infected individuals.

The Atahualpa Project is an ongoing population-based prospective cohort study aimed to assess the burden of sleep disorders and cerebrovascular diseases among community dwellers living in rural Ecuador [11] . During the past nine years, the adult population of Atahualpa has undergone several interviews and procedures for assessing breathing and non-breathing sleep-related disorders, cardiovascular risk factors and other conditions of interest [12] [13] [14] [15] .

Atahualpa was severely struck by the SARS-CoV-2 pandemic from March to May 2020, with a mortality rate of 21.6 per 1,000 population [16] , a seroprevalence of 45% among survivors [17] , and an incidence rate ratio of 7.4 per 100 person months of potential virus exposure [18] . Taking the unique opportunity of this well-established cohort, the present longitudinal A c c e p t e d M a n u s c r i p t 5 prospective study aimed to assess changes in sleep quality (before and after the peak of the pandemic) among individuals with and without evidence of SARS-CoV-2 infection.

Atahualpa residents are homogeneous in terms of race/ethnicity, dietary habits, socioeconomic status and lifestyles, as detailed elsewhere [19] . Minimal migration rate of the population together with the high adherence to the project, make this village an optimal setting for the conduction of cohort studies [20] . In addition, these individuals share important characteristics for the study of sleep-related symptoms that reduce the chance of unexpected confounders. These include exposure to 12 daily hours of sunlight all over the year, hot and dry weather, virtually no shift working, and limited nighttime light pollution.

Atahualpa residents aged ≥40, previously identified by means of door-to-door surveys, were eligible for the present study if they have had assessment of sleep quality in the year before the start of the pandemic (by the use of the PSQI), and a serological test for identification of SARS-CoV-2 IgM and IgG by the use of a lateral flow-based SARS-CoV-2 antibody testing (BIOHIT Health Care Ltd., Cheshire, UK) in two rounds performed on May and June, 2020 [17, 18] . Candidates were identified by a new door-to-door survey conducted on October, 2020. In this new visit, a repeated PSQI was completed by the same trained field personnel that performed previous tests. In addition, individuals who were seronegative for SARS-CoV-2 in the previous two surveys were specifically asked for the occurrence of clinical manifestations suggestive of COVID-19 (World Health Organization operational definitions of suspected cases were used [21] ), and those who gave a positive answer underwent a repeated lateral flow-based antibody testing to assess for more recent infections. Those who only had IgM antibodies (associated or not with a weak IgG response) were excluded from Social factors inherent to the pandemic itself were also included as covariates. These included home confinement, social isolation (living alone), and having a bed partner with SARS-CoV-2 infection (irrespective of the serological status of the index bed partner). All the abovementioned covariates had been updated during the surveys assessing SARS-CoV-2 seropositivity in villagers (two-to-three months after the start of the pandemic) [17, 18] . Therefore, we used those measures and determinations for analyses as they represented a midpoint between retrospective and prospective PSQI evaluations of this study (coinciding with the exposure). were confined to home during the peak of the pandemic (April to June), and 202 (32%) had a bed-partner with SARS-CoV-2 infection.

Using the PSQI cutoff of >5 points for defining poor sleep quality, 185 (29%) individuals at baseline, and 311 (49%) at the time of the follow-up PSQI, were "poor sleepers" (p<0.001).

In univariate analysis, individuals who remained in the category of "good sleepers" across baseline and follow-up PSQI were more commonly SARS-CoV-2 seronegative (47% versus 35%; p=0.001). On the other hand, individuals who moved from the category of "good sleeper" to that of "poor sleeper" in the follow-up, were more often SARS-CoV-2 seropositive (38% versus 22%; p<0.001). Table 1 Progression from good to poor sleep quality as well as increases in the PSQI in the follow-up are higher among seropositive individuals than in their seronegative counterparts.

As previously mentioned, no single study has prospectively evaluated changes in sleep quality before and after the start of the SARS-CoV-2 pandemic in community-dwellers according to whether or not they were infected with the virus. Therefore, our results are not comparable to previous works. Nevertheless, some pieces of information can be extracted from published data. A Chinese study investigated the frequency of poor sleep quality and its stressors in apparently healthy subjects during the peak of the SARS-CoV-2 pandemic (assessment was conducted by means of an online survey only); about one third of participants had a poor sleep quality that was mediated by perceived stress, anxiety levels, A c c e p t e d M a n u s c r i p t 11 and low self-esteem [25] . Another online study conducted in China, also during the peak of the pandemic, disclosed sleep disturbances in about 18% of respondents. However, participants were not specifically inquired on whether they had SARS-CoV-2 infection or not. In that study, self-perceived health conditions were major factors favoring a poor sleep quality [9] . A Norwegian online survey, involving healthy subjects from a fitness center disclosed sleep disturbances in about 22% of individuals, which was significantly associated with decreased physical activity and psychological distress [26] . In general, thoseand other studies focused on the decreased sleep quality observed in populations under the threat of SARS-CoV-2 infection, as well as on the importance of a good mental health for reducing the risk of sleep-related symptoms. None of them attempted to assess whether there has been a measured change in sleep quality before and after the peak of the SARS-CoV-2 pandemic. To our knowledge, only one study from Nepal suggested that sleep disordersmostly insomnia were more frequently reported after the start than before the pandemic; however, such study collected data by means of an online cross-sectional survey asking about sleep symptoms occurring in the past, and such design could be flawed by a recall bias [27] .

Our findings disclose a potentially important, yet non-explored, aspect of the relationship between sleep quality and SARS-CoV-2 infection. While the population at large experience a small degree of sleep quality deterioration during the pandemic (likely related to the abovementioned psychological consequences), individuals infected by the virus have a more severe deterioration in sleep quality than their non-infected counterparts (after adjusting for stressors and risk factors).

The above-mentioned results suggest a direct (and late) effect of the virus itself on the anatomical pathways related to sleep. In this view, direct invasion of the central nervous system by SARS-CoV-2 is plausible since the receptor used by the virus for cell entryangiotensin-converting enzyme-2is expressed in neurons and glial cells [28] . This A c c e p t e d M a n u s c r i p t 12 neurotropism may be the cause of sleep-related symptoms as well as other neurological complications that, according to a recent comprehensive review includebut are not limited tostroke, encephalitis (or diffuse encephalopathy), myelitis, and peripheral or cranial neuropathies [29] . In addition, many patients develop anosmia-ageusia or non-specific headaches. However, knowledge on these complications is still limited and pathogenetic mechanisms involved in the development of COVID-19-related neurological complications are complex and not fully-understood thus far [29] [30] [31] .

Entry of SARS-CoV-2 into the CNS through the nasal olfactory epithelium and, from then, to the olfactory bulb, facilitates further spread of the virus by trans-synaptic transfer to limbic structures and subsequently to deeper parts of the brain. An alternative theory proposes entrances of the virus to the CNS directly from the bloodstream through the blood brain barrier [32] . In any case, presence of the virus within the CNS may explain the disruption of structures involved in the anatomy of sleep, such as periventricular fibers connecting the frontal lobes with nuclei deep in the brain (basal ganglia, thalamus and hypothalamus) [33] .

Studies using Positron Emission Tomography CT support this possibility by showing abnormal fluorine-18 Fluorodeoxyglucose uptake (hypometabolism) in limbic structures, frontal and orbito-frontal cortex, the cingulate gyrus, and the thalamus/hypothalamus among COVID-19 survivors [34] .

The present study provides the unique opportunity to prospectively evaluate sleep qualityby means of an internationally accepted field instrumentin an unbiased population of middle-aged and older adults that have such evaluation before and several months after the establishment of the SARS-CoV-2 pandemic in the village. Another strength of this study includes the high coverage of long-term participants in the Atahualpa Project cohort, in whom several risk factors have been well characterized. Nevertheless, the study has limitations. The lateral flow-based antibody test we used is reported to have high sensitivity A c c e p t e d M a n u s c r i p t 13 and specificity, but we cannot rule out a small degree of misclassification due to false positive or false negative results [17, 18] . In addition, assessment of SARS-CoV-2 status at the time of the follow-up PSQI was only investigated in individuals with symptoms of recent onset, and there is the possibility that some seropositive-asymptomatic individuals may had escaped detection. The PSQI is reliable and has been widely validated, but it is mostly based on the subjective assessment of sleep quality and the time-frame of such evaluation is in the month before the test. Despite the above-mentioned limitations, this is the single study proving information on sleep quality before and after the peak of the pandemic in a population highly endemic for SARS-CoV-2. The use of actigraphy, for a more objective evaluation of non-breathing sleep-related manifestations (sleep hours and sleep efficiency), is strongly recommended. In addition, other well-established population-based cohorts in whom participants have had sleep quality assessments before the SARS-CoV-2 pandemic, should be encouraged to obtain data after the start of the pandemic in their given populations to confirm our findings by assessing potential detriments in sleep quality among those who were infected.

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