For hundreds of years, people have observed that asthma severity often worsens in the nighttime. One longstanding question has been to what degree the body’s internal circadian clock — as opposed to behaviors, such as sleep and physical activities — contributes to worsening of asthma severity. Using two circadian protocols, investigators from Brigham and Women’s Hospital and Oregon Health & Science University have pinned down the influence of the circadian system, uncovering a key role for the biological clock in asthma. Understanding the mechanisms that influence asthma severity could have important implications for both studying and treating asthma. Results are published in The Proceedings of the National Academy of Sciences.
“This is one of the first studies to carefully isolate the influence of the circadian system from the other factors that are behavioral and environmental, including sleep,” said co-corresponding author Frank A.J.L. Scheer, PhD, MSc, director of the Medical Chronobiology Program in the Division of Sleep and Circadian Disorders at the Brigham. Co-corresponding author Steven A. Shea, PhD, professor and director at Oregon Institute of Occupational Health Sciences added, “We observed that those people who have the worst asthma in general are the ones who suffer from the greatest circadian-induced drops in pulmonary function at night, and also had the greatest changes induced by behaviors, including sleep. We also found that these results are clinically important because, when studied in the laboratory, symptom-driven bronchodilator inhaler use was as much as four times more often during the circadian night than during the day.”
As many as 75 percent of people with asthma — 20 million people in the U.S. — report experiencing worsening asthma severity at night. Many behavioral and environmental factors, including exercise, air temperature, posture, and sleep environment, are known to influence asthma severity. Scheer, Shea, and colleagues wanted to understand the contributions of the internal circadian system to this problem. The circadian system is composed of a central pacemaker in the brain (the suprachiasmatic nucleus) and “clocks” throughout the body and is critical for the coordination of bodily functions and to anticipate the daily cycling environmental and behavioral demands.
To disentangle the influence of the circadian system from that of sleep and other behavioral and environmental factors, the researchers enrolled 17 participants with asthma (who were not talking steroid medication, but who did use bronchodilator inhalers whenever they felt asthma symptoms were worsening) into two complementary laboratory protocols where lung function, asthma symptoms and bronchodilator use were continuously assessed. In the “constant routine” protocol, participants spent 38 hours continuously awake, in a constant posture, and under dim light conditions, with identical snacks every two hours. In the “forced desynchrony” protocol, participants were placed on a recurring 28-hour sleep/wake cycle for a week under dim light conditions, with all behaviors scheduled evenly across the cycle.
Both protocols helped to uncover that participants with asthma had their lowest lung function during the circadian night, around 4 a.m., and a worsening of asthma that normally may be “hidden” during sleep. Using a mathematical model, the team found that there were additive influences from the circadian system and the behavioral sleep/wake cycle, suggesting that both circadian and sleep effects may contribute to worsening asthma severity.
“Our findings point to a phenomenon of ‘silent’ asthma,” said Scheer. “A person’s airway resistance may be worse at night, due to the combined effects of the circadian system and of the behavioral sleep/wake cycle, but they are generally unaware of this unless it is so severe that it wakes them up.”
The team acknowledges limitations of their study, including the need to study the influence of additional behaviors such as exercise and temperature changes, and testing the generalizability of their findings to patients taking other medications for asthma such as inhaled corticosteroids.
“These highly standardized protocols revealed that the internal circadian system plays a significant role in modulating lung function and asthma severity, and that these influences summate with other daily behavioral and environmental effects to drive asthma to be worst at night,” said Scheer. “Uncovering a key role of the biological clock in asthma severity may help in the development of novel therapeutic approaches for asthma,” concluded Shea.
Conflict of Interest Disclosures:
Funding: This work was supported by the National Institutes of Health (grants R01HL064815, R35 HL155681, R01HL118601, M01RR02635, UL1TR002541) and Oregon Institute of Occupational Health Sciences at Oregon Health & Science University via funds from the Division of Consumer and Business Services of the State of Oregon (ORS 656.630).
Paper cited: Scheer F.A. et al. “The Endogenous Circadian System Worsens Asthma at Night Independent of Sleep and Other Daily Behavioral or Environmental Cycles” PNAS 10.1073/pnas.2018486118
