Sleep disorders of post-COVID-19 conditions

Dear Editor,

To date, a large number of patients with COVID-19 infection have “recovered” from the acute phase of the illness. However, a significant proportion of recovered patients worldwide have persistent or emerging symptoms which are clinically diverse. The World Health Organization (WHO) has recognized this cluster of symptoms as a new condition, often referred to as long COVID and also known as the post-COVID-19 condition (PCC). PCC occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.

Symptoms related to sleep disorders are common sequelae of COVID-19. Through the analysis of data in the literature, we have a preliminary understanding of the prevalence of post-COVID-19 sleep problems. An online survey (including 3726 participants from 56 countries) showed that the prevalence of sleep disorders during follow-up over 7 months reached 78.6%, including insomnia (60%), night sweats (41%), awakening feeling unable to breathe (36%), restless legs (18%), and sleep apnea (10%) [1]. In a registry study of 236,379 COVID-19 survivors, about one-third of them received a neuropsychiatric diagnosis (such as stroke, dementia, insomnia, anxiety, and emotional disorders) within 6 months of the first symptoms of COVID-19, which is 44% higher than reported for influenza survivors [2].

Due to the complexity and diversity of PCC symptoms, there is currently no clear pathophysiological explanation of its causes. Immune metabolism-neuroinflammation may play a key role in PCC sleep disorders. The disturbance of neurotransmitters and metabolites produced by intestinal microorganisms and intestinal endocrine cells or intestinal chromaffin cells leads to a continuous increase in proinflammatory cytokine levels (e.g., CRP, IL-1, IL-6, TNF-α, ferritin, and D-dimer). Intestinal leakage may lead to the development of a cytokine storm in patients with COVID-19 and induce brain neuroinflammation through the blood circulation, thus affecting the sleep–wake function. PCC may also include behavioral changes that include social disinterest, isolation, reduced physical activity, fatigue, increased sleep duration, lethargy, and reduced appetite. PCC may be an adaptive, evolutionarily conserved response to infectious diseases, conserving energy to boost the immune system’s efficiency. Immune dysfunction caused by COVID-19 may disrupt microbial balance and cytokine responses. Any persistent infection or inflammatory response that drives the neuroimmune signals of the afferent vagus nerve can activate the dorsal glial cells resulting in the persistence of symptoms [3].

Symptoms of sleep disorders share many characteristics with neuropsychiatric conditions, including fatigue, cognitive dysfunction, decreased concentration, paresthesia, anxiety, and depression, which are also common PCC symptoms. There are many possible factors contributing to PCC sleep disturbance, such as gender (more females than males), age, severity of illness, chronic disease, socioeconomic status, social isolation, loneliness, circadian rhythm disturbance, and mental disorders (e.g., tension, worry, fear, anxiety, depression). Sleep disturbances may lead to a number of functional consequences, such as reduced productivity, substantial work costs, and increased health care costs. Therefore, there is an urgent need for effective intervention.

Some research has focused on the treatment of PCC sleep disorders, but there are few reports in the literature. Two randomized controlled trials have shown that hyperbaric oxygen therapy (HBOT) may induce neuroplasticity and improve cognitive, mental, fatigue, sleep, and pain symptoms in patients with PCC. The beneficial effects of HBOT may be attributed to altered functional connectivity of neural pathways in areas associated with cognitive and emotional roles [4, 5]. Probiotics have been recommended to regulate the gut microbiome and correct the microbiome-intestine-brain axis to improve neuropsychiatric complications in patients with PCC.

Prior to the COVID-19 epidemic, the worldwide prevalence of sleep disorders was substantial. Given the large global population infected with COVID-19, the prevalence of sleep disorders is very likely to increase. Therefore, it is justifiable to direct more resources to investigate epidemiological factors, pathophysiologic mechanisms, and interventional strategies for sleep disorders associated with PCC.

Data availability

Not applicable.

Declarations

Ethical approval

This report does not involve human subjects and patients with data.

Conflict of interest

The authors declare no competing interests.