Most asthma sufferers will know their symptoms are often worse at night, and this phenomenon has been observed for centuries. But why is this the case? A fascinating new study has put more than a dozen asthma patients through two rigorous experiments and found the body’s circadian clock may be responsible.
In 1698 English physician Sir John Floyer published a monograph titled A Treatise of the Asthma. It was one of the first robust investigations into this common disease, and one of Floyer’s key observations was that asthma episodes tend to more frequently occur late at night, leading to the condition being informally referred to as "nocturnal asthma."
Up to three-quarters of asthmatics report worsening of symptoms at night and the phenomenon is often thought to be due to a variety of behavioral and environmental factors, including posture changes, air temperature and sleep environment.
Some researchers have also speculated circadian rhythms may play a role in the ebbs and flows of asthma flare-ups. We know our central body clock influences a variety of physiological processes, but researchers have never fully homed in on the effect of the circadian system on asthma severity.
"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," explains Frank Scheer, co-corresponding author on the new study.
To isolate the effect of circadian cycles on asthma the researchers conducted two thorough laboratory studies on 17 people with asthma. The first experiment was called a “constant routine” test.
Here the participants were kept awake for 38 hours in consistent dim light conditions. The cohort maintained a fixed sitting posture for the 38-hour stretch and consumed the same caloric snack every two hours.
The goal of this first experiment was to eliminate as many behavioral and environmental factors as possible, allowing for a direct investigation of circadian rhythmicity on asthma symptoms.
The second experiment was dubbed “forced desynchrony” and placed the cohort into a seven-day, 28-hour sleep/wake cycle with daily behaviors evenly scheduled across individual 28-hour days.
This lasted 196 hours and was designed to effectively decouple daily behaviors from internal 24-hour circadian cycles. So by the end of the experiment, sleep and eating phases were entirely separated from circadian rhythms.
Both experiments revealed circadian rhythms play a significant role in regulating pulmonary function over a daily cycle. Interestingly, the forced desynchrony experiment revealed sleep phases do play a notable role in asthma severity independent of circadian effects.
However, the influence of circadian cycles on asthma was just as relevant as sleep/wake behavioral cycles, and the lowest pulmonary functions were detected at around the circadian equivalent of 4 am. So the ultimate reason asthma seems to be worse at night is due to a relatively even combination of sleep behaviors and circadian cycles.
"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,” says Steven Shea, co-corresponding author on the study. “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."
Although the study offers robust confirmation of the role endogenous circadian rhythms have on asthma severity it is still not known why this is the case. The researchers speculate an array of mechanisms are known to ebb and flow with circadian cycles, but more work will be needed to home in on which specific underlying processes are influencing asthma. Hypothesized mechanisms include everything from circadian variations in histamine and melatonin levels to daily oscillations in immune cells.
"Our studies have enabled us to statistically separate the independent contributions of circadian versus behavioral and environmental influences on pulmonary function,” the researchers conclude in the study. “These results may be important, as they could point to separate targets for therapy. Specifically, therapeutics directed at the circadian system can potentially include timed light exposure or timed pharmaceuticals to improve effectiveness, reduce side effects, or influence central or peripheral circadian clocks themselves.”
The new study was published in the journal PNAS.
Source: Brigham and Women’s Hospital
