Brigham researchers are tackling long COVID from every angle, addressing critical questions about how the condition affects wide-ranging aspects of health and laying the groundwork for preventing and treating symptoms. This story is a part of a series about the efforts happening across Mass General Brigham to understand, treat and prevent long COVID.

Susan Redline

As the lingering effects of COVID-19 infections have become clearer, researchers are working to untangle the complex web of associations between sleep disorders, inflammation, acute COVID-19 and long COVID.

Though it has been challenging to uncover these hidden connections, the motivation to improve patient experiences is high: sleep disturbances are prevalent, affecting 34 to 50 percent of patients with long COVID. Patients report a range of conditions from insomnia to hypersomnia, excessive daytime sleepiness to a fluctuation between the two.

But does long COVID lead to sleep disturbances or do sleep disturbances predispose people to long COVID? Or both?

Susan Redline, MD, MPH and her colleagues in the Brigham’s Division of Sleep and Circadian Disorders are working closely with RECOVER, a National Institute of Health (NIH) funded effort to understand the risk factors for long COVID. Their efforts may help us understand the relationship between sleep and long COVID.

“Sleep disturbances are an excellent potential candidate to explain susceptibility to long COVID because sleep itself is an essential pillar of health,” Susan Redline, MD, MPH, of the Brigham Department of Medicine and Neurology’s Division of Sleep and Circadian Disorders said. “Sleep is a critical factor that influences our body’s ability to create immune responses and influences the general health of the heart, lungs and brain.”

Teasing Apart Relationships

Brian Cade

At the height of the pandemic, Brian Cade, PhD, of the Brigham Division of Sleep and Circadian Disorders, was curious if sleep disorders might be one such risk factor for acute COVID-19 infections. He led research to understand the connection prior to the advent of RECOVER, piloting the use of electronic medical record data.

“We now know that sleep disturbances and disorders like sleep apnea are associated with increased risk of adverse acute COVID-19 outcomes, including admission to the ICU, mechanical ventilation or death independent of demographics,” Cade said. “The jury is still out about whether there is causation, and whether this is bidirectional, but we have some clues.”

The team has generated a few hypotheses: sleep apnea is associated with other disease like type 2 diabetes that mediate the link to severe COVID-19 infection and mortality, and could work indirectly through them. Sleep apnea is also associated with increased risk of micro aspirations, or changes to breathing from saliva being absorbed into the airway, that might directly increase risk of infection. This hypothesis is supported by Cade’s team preliminary finding that patients who used a treatment for sleep apnea – CPAP, or continuous positive airway pressure used to keep the airway open – in the year before their COVID-19 diagnosis had reduced adverse events like ICU admission, mechanical ventilation or death.

Still, understanding the mechanistic link is challenging because of the many variants of the illness.

“Early on, all these associations were with pre-Delta variants,” Cade said. “If you look at periods of time where Omicron was the most prevalent variant in the Boston region, based on the Broad Institute’s data, the associations are changing. Mechanistically, it’s possible there are different changes with the upper and lower airway between the two variants.”

While Cade’s research used data from the Mass General Brigham Biobank, RECOVER offers a much larger and more longitudinal dataset to tease apart the relationship between sleep and long COVID. Patients are first screened for sleep disturbances through questionnaires, physical exams and data from wearable devices (like Fitbits). If patients screened positively, they participated in overnight home sleep studies that measure overall oxygenation, breathing and sleep apnea. Then, based on those results, patients participated in additional studies.

Redline recently collaborated on a project conducted by the RECOVER (REsearching COVID to Enhance Recovery) initiative that found that patients with sleep apnea had up to a 75% increased risk of long COVID. Now her team is working with the RECOVER cohort to prospectively collect sleep data in individuals with and without long covid to better understand the role of sleep problems influencing the risk of long Covid and recovery from Covid infection.

“The data can be used to examine past risk factors for COVID and also give individual patients feedback so they can pursue interventions to help them,” Redline explains.

Addressing Patients’ Concerns

Patients are eager for this information and Redline says engaging patients and families who are suffering is a key priority for investigators at the Brigham and the NIH who recognize the urgency to come up with solutions.

“Sleep disorders are so prevalent in people with long COVID and disproportionately affect individuals from populations who are socially disadvantaged or underserved in health care,” Redline explains. “Sleep is relevant for how the body responds to an acute viral illness, especially one that generates inflammation. But we still have knowledge gaps in terms of how many of these disorders preceded COVID versus followed COVID.”

Given the rapidly changing science and difficulty pinpointing a single mechanism that can be pharmacologically targeted, progress can be slow.

“I know patients and families are frustrated by the pace of progress, and I share that frustration — we want to get to treatment quickly, but we need to build a foundation of evidence first. It begins with defining long COVID, understanding why people develop long COVID and then identifying well-informed interventions.”

Since multiple, interrelated aspects of different sleep disorders could be targeted, interventions are being considered that address multiple ways sleep and daytime sleepiness may be improved.

“As we shape the future of care for patients with long COVID, there’s opportunity for better recognition and treatment of sleep problems both clinically and on a population level,” Redline said, highlighting the synergistic relationship between these two areas of research.

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