INTRODUCTION
Post-acute COVID-19 syndrome (PASC) is a global public health crisis in which patients experience lingering and debilitating symptoms beyond 4 weeks after the acute onset of SARS-CoV-2 infection.1 Sleep disturbance has a reported prevalence of 34–50% in PASC,2,3 but only a few studies have identified associated risk factors, and these have primarily described sleep quality and not symptom severity.3,4 Likewise, studies to date have not investigated the interaction of mood disorders and fatigue with sleep disturbance severity or the association of objective sleep study indices in PASC.
METHODS
Patients with PASC1 were evaluated at the Cleveland Clinic ReCOver Clinic between February 2021 and April 2022. Patients ≥ 18 years old who completed Patient-Reported Outcomes Measurement Information System (PROMIS)5 Sleep Disturbance within 90 days or during their initial ReCOver clinic visit were prospectively examined. Demographics and clinical characteristics were extracted from the COVID-19 Cleveland Clinic Registry. In a subset with pre-infection sleep studies available, Apnea Hypopnea Index (AHI) and hypoxia measures (mean oxygen saturation [SaO2%] and percentage of time spent < 90% oxygen saturation [T90]) were extracted. Patient-reported outcomes collected during the initial ReCOver clinic visit from the Electronic Medical Record included PROMIS Sleep Disturbance, Fatigue, and Global Health (PROMIS-GH) v1.2, Generalized Anxiety Disorder (GAD)-2, Patient Health Questionnaire (PHQ)-2, and the Quality of Life in Neurological Disorders (Neuro-QoL) v1.0 Cognitive Function. PROMIS scores were standardized on a T-scale with mean 50 (SD 10)6, with established cut-points at > 55, > 60, and > 70 for mild, moderate, and severe sleep disturbance respectively.6 Multivariable models were constructed to identify independent predictors of moderate to severe sleep disturbances based on clinically relevant variables determined a priori. Interactions between mood disorders and fatigue using PROMIS Fatigue, PHQ-2, and GAD-2 scores were tested.
RESULTS
A total of 962 of 1660 patients completed the PROMIS Sleep Disturbance; 565 (58.7%) had normal to mild sleep disturbance and 397 (41.3%) had moderate to severe sleep disturbance with characteristics shown in Table 1. After adjustment (Table 2), Black race (OR = 1.84, 95%CI: 1.10–3.08, p = 0.020), hospitalization for COVID-19 (OR = 1.59, 95%CI: 1.10–2.32, p < 0.015), greater anxiety severity (OR = 1.31, 95%CI: 1.18–1.45, p < 0.001), and moderate to severe fatigue (OR = 2.03, 95%CI: 1.33–3.11, p = 0.001) were significantly associated with moderate to severe sleep disturbance. Statistical interactions of anxiety severity and moderate to severe fatigue were not significant (p = 0.84).
Table 1.
Patient Characteristics Stratified by Normal/Mild Versus Moderate/Severe Sleep Disturbance
| Characteristic | Total (N = 962) |
Normal/mild sleep disturbance (N = 565) |
Moderate/severe sleep disturbance (N = 397) |
p-value |
|---|---|---|---|---|
| Age | 49.6 ± 13.7 | 50.0 ± 14.5 | 49.1 ± 12.5 | 0.31a2 |
| Gender | 0.41c | |||
| Female | 721 (74.9) | 418 (74.0) | 303 (76.3) | |
| Male | 241 (25.1) | 147 (26.0) | 94 (23.7) | |
| Race | 0.003c | |||
| White | 788 (81.9) | 483 (85.5) | 305 (76.8) | |
| Black | 125 (13.0) | 60 (10.6) | 65 (16.4) | |
| Other | 49 (5.1) | 22 (3.9) | 27 (6.8) | |
| BMI (kg/m2)* | 31.6 ± 7.7 | 31.2 ± 7.5 | 32.1 ± 8.0 | 0.11a1 |
| Time since positive test, (months) | 6.7 ± 4.2 | 6.8 ± 4.2 | 6.5 ± 4.2 | 0.28a1 |
| Comorbidities | ||||
| Asthma | 149 (15.5) | 79 (14.0) | 70 (17.6) | 0.12c |
| Chronic fatigue | 4 (0.42) | 2 (0.35) | 2 (0.50) | 0.99d |
| COPD | 21 (2.2) | 12 (2.1) | 9 (2.3) | 0.88c |
| Coronary artery disease | 28 (2.9) | 12 (2.1) | 16 (4.0) | 0.083c |
| Dementia | 1 (0.10) | 0 (0.00) | 1 (0.25) | 0.41d |
| Diabetes | 77 (8.0) | 38 (6.7) | 39 (9.8) | 0.081c |
| Heart failure | 13 (1.4) | 8 (1.4) | 5 (1.3) | 0.84c |
| Hypertension | 202 (21.0) | 118 (20.9) | 84 (21.2) | 0.92c |
| Interstitial lung disease | 3 (0.31) | 0 (0.00) | 3 (0.76) | 0.070d |
| Obesity | 85 (8.8) | 52 (9.2) | 33 (8.3) | 0.63c |
| Pulmonary embolism | 21 (2.2) | 12 (2.1) | 9 (2.3) | 0.88c |
| Pulmonary hypertension | 5 (0.52) | 5 (0.88) | 0 (0.00) | 0.081d |
| Systemic lupus erythematosus | 9 (0.94) | 3 (0.53) | 6 (1.5) | 0.17d |
| COVID-19 severity | ||||
| Hospitalization | 0.017c | |||
| Missing | 16 (1.7) | 10 (1.8) | 6 (1.5) | |
| No | 683 (71.0) | 420 (74.3) | 263 (66.2) | |
| Yes | 263 (27.3) | 135 (23.9) | 128 (32.2) | |
| Intensive care unit stay | 0.98c | |||
| Missing | 13 (1.4) | 8 (1.4) | 5 (1.3) | |
| No | 898 (93.3) | 527 (93.3) | 371 (93.5) | |
| Yes | 51 (5.3) | 30 (5.3) | 21 (5.3) | |
| Mechanical ventilation | 0.99c | |||
| Missing | 14 (1.5) | 8 (1.4) | 6 (1.5) | |
| No | 929 (96.6) | 546 (96.6) | 383 (96.5) | |
| Yes | 19 (2.0) | 11 (1.9) | 8 (2.0) | |
| Patient-reported outcomes | ||||
| GAD-2* | 2.2 ± 2.0 | 1.7 ± 1.7 | 3.0 ± 2.1 | < 0.001a2 |
| PHQ-2* | 2.1 ± 1.9 | 1.6 ± 1.6 | 2.7 ± 2.0 | < 0.001a2 |
| PROMIS Global Mental Healthɫ* | 41.5 ± 9.2 | 44.0 ± 8.8 | 37.9 ± 8.6 | < 0.001a1 |
| PROMIS Global Physical Healthɫ* | 39.7 ± 8.6 | 42.1 ± 8.3 | 36.2 ± 7.7 | < 0.001a1 |
| PROMIS fatigue* | 62.7 ± 9.1 | 60.2 ± 8.8 | 66.2 ± 8.2 | < 0.001a1 |
| Moderate/severe fatigue* | 593 (67.2) | 294 (57.1) | 299 (81.5) | < 0.001c |
| Severe fatigue* | 192 (21.8) | 64 (12.4) | 128 (34.9) | < 0.001c |
| PROMIS Sleep Disturbance | 57.8 ± 8.4 | 52.3 ± 5.3 | 65.5 ± 5.3 | < 0.001a1 |
| Neuro-QoL Cognitive Function* | 39.4 ± 10.0 | 41.6 ± 10.0 | 36.4 ± 9.2 | < 0.001a1 |
| Sleep study variables (N = 48) | ||||
| Study type | 0.61d | |||
| Home sleep apnea test | 44 (91.7) | 22 (95.7) | 22 (88.0) | |
| Polysomnogram | 4 (8.3) | 1 (4.3) | 3 (12.0) | |
| AHI total | 15.4 ± 18.9 | 18.7 ± 24.4 | 12.4 ± 11.8 | 0.27a2 |
| Mean oxygen saturation (%)* | 92.0 ± 2.3 | 91.5 ± 2.8 | 92.5 ± 1.6 | 0.14a2 |
| % Sleep time O2 < 90 (T90)* | 12.1 [2.8,73.3] | 16.5 [3.5, 83.2] | 9.3 [1.8, 44.3] | 0.32a2 |
BMI, body mass index; COPD, chronic obstructive pulmonary disease; GAD-2, Generalized Anxiety Disorder-2; PHQ-2, Patient Health Questionaire-2; PROMIS, Patient-Reported Outcomes Measurement Information System
*Data not available for all subjects. Missing values: BMI (kg/m2) = 90; GAD-2 = 136; PHQ-2 = 135; PROMIS Global Mental Health = 38; PROMIS Global Physical Health = 30; PROMIS Fatigue = 80; moderate/severe fatigue = 80; severe fatigue = 80; Neuro-QoL Cognitive Function = 126; mean oxygen saturation (%) = 1; sleep time O2 under 90 (%) = 2
ɫHigher scores indicate better health/functioning
Comparisons across sleep disturbance categories were made using Pearson’s chi-square test or Fisher’s exact test for categorical variables and t-test for continuous variables
Statistics presented as mean ± SD, N (column %). p-values: a1 = t-test, a2 = Satterthwaite t-test, c = Pearson’s chi-square test, d = Fisher’s exact test
Table 2.
Multivariable Logistic Regression Model for Predicting Moderate/Severe Sleep Disturbance
| Predictor | Odds ratio (95% CI) | p-value |
|---|---|---|
| Age (per decade) | 1.00 (0.88, 1.14) | 0.97 |
| Female | 0.95 (0.64, 1.39) | 0.78 |
| Race (reference = White) | ||
| Black | 1.84 (1.10, 3.08) | 0.020 |
| Other | 1.93 (0.95, 3.93) | 0.069 |
| BMI (per 5 kg/m2) | 1.05 (0.94, 1.17) | 0.41 |
| Hospitalization for COVID-19 | 1.59 (1.10, 2.32) | 0.015 |
| PHQ-2 | 1.08 (0.96, 1.21) | 0.20 |
| GAD-2 | 1.31 (1.18, 1.45) | < 0.001 |
| Moderate/severe fatigue | 2.03 (1.33, 3.11) | 0.001 |
| Neuro-QoL Cognitive Function | 0.99 (0.96, 1.01) | 0.21 |
CI, confidence interval; BMI, body mass index; PHQ-2, Patient Health Questionnaire-2; GAD-2, generalized anxiety disorder-2
Forty-eight patients had pre-COVID-19 sleep testing conducted 2.6 ± 2.1 years prior to the initial ReCOver Clinic appointment. AHI, the primary measure of obstructive sleep apnea (OSA) severity, was 15.4 ± 18.9 with mean SaO2 of 92 ± 2.3% and a median T90% of 12.1 [2.8,73.3] (Table 1). OSA (AHI:18.7 ± 24.4 vs 12.4 ± 11.8, p = 0.27) and hypoxia measures (mean SaO2%: 91.5 ± 2.8 vs 92.5 ± 1.6, p = 0.14; median T90% 16.5 [3.5, 83.2]vs 9.3 [1.8, 44.3], p = 0.32) were not statistically different between normal to mild and moderate to severe sleep disturbance.
DISCUSSION
Novel findings include a high prevalence of 41.3% of moderate to severe sleep disturbance in PASC associated with Black race, hospitalization for COVID-19, anxiety severity, and moderate to severe fatigue. There was no significant interaction between anxiety severity and moderate to severe fatigue; further studies are needed to investigate the interplay between mental and sleep disturbances in PASC physiologic pathways. Likewise, there was no association between objective sleep study measures of antecedent sleep apnea and hypoxia with sleep disturbance. This may be explained by the small sample size, testing indication biases, or limitations of sleep study type (i.e., home sleep apnea test), precluding assessment of objective sleep quality or quantity measures. With 58% of PASC patients completing PROMIS Sleep Disturbance, our study may suffer from selection bias. However, we observed that among patients of Black race who did not complete PROMIS Sleep Disturbance, 60% completed mood and fatigue questionnaires. As such, it is possible that the magnitude of association between Black race and moderate to severe sleep disturbances is even stronger. Study findings emphasize the importance of identification of sleep disturbance in PASC considering its impact on patients’ quality of life, daytime functioning, and medical health status. Results inform risk stratification and highlight the need to elucidate contributions of structural racism and socioeconomic inequities to PASC-related sleep disturbances with the goal of developing interventions to reduce PASC disparities.
Author Contribution
All authors have seen and approved the manuscript.
Funding
Neuroscience Transformative Research Resource Development Award. This award funded the collection and management of the sleep study registry.
Data Availability
The data that support the findings of this study are available on request from the corresponding author.
Declarations
Conflict of Interest
The authors have no financial conflicts of interest.
Footnotes
Publisher's Note
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Associated Data
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Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author.