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
Table 2 Multivariable Logistic Regression Model for Predicting Moderate/Severe Sleep Disturbance

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.