Circadian system contributes to asthma severity during sleep

Researchers found that the circadian system contributes to the common nighttime worsening of asthma, according to data published in Proceedings of the National Academy of Sciences of the United States of America.

“For centuries, it has been recognized that asthma severity shows a daily rhythm, with the worst symptoms at night,” Frank A.J.L. Scheer, MSc, PhD, of the division of sleep medicine at Harvard Medical School, and colleagues wrote. “However, it is unclear to what degree this is driven by everyday behaviors, such as sleep, physical activity and body posture changes, versus intrinsic rhythms generated by the internal body clock.”

Scheer and colleagues wrote that the body’s circadian system may influence the pulmonary and inflammatory system via the automatic nervous system, humoral factors and local molecular clocks.

To determine the independent effect of the endogenous circadian system on asthma, the researchers enrolled patients with asthma without steroid use and a group of control participants in two complementary in-laboratory protocols.

The protocols included a 38-hour “constant routine” (CR) — designed to estimate circadian rhythmicity in asthma severity without environmental and behavioral changes — which involved continuous wakefulness during semi-recumbent rest in dim-light conditions and fixed-interval isocaloric intake. Also, a 196-hour “forced desynchrony” (FD) protocol involved all behaviors scheduled evenly across the circadian cycle in dim-light conditions.

Additionally, the researchers measured pulmonary function per day during a 3-week ambulatory protocol to compare circadian rhythms in asthma severity with daily at-home behavioral and environmental conditions.

Seventeen patients (10 women; mean age, 26.5 years; BMI, 24.3 kg/m²) completed the ambulatory protocol, 11 of whom completed the CR protocol and 13 of whom completed the FD protocol. Ten control participants (8 women; mean age, 28 years; BMI, 25.3 kg/m²) completed the ambulatory and CR protocols, five of whom completed the FD protocol.

Evaluation of data from the FD protocol showed no significant differences between those with asthma and those in the control group in terms of the endogenous circadian period, time of core body temperature, habitual waketime, and the time between minimum core body temperature and habitual waketime.

During the ambulatory protocol, the patients with asthma had an average forced expired volume in 1 second (FEV₁) of 75% of the predicted pulmonary function value expected in asymptomatic participants based on height, age and sex, compared with 100% in the control group (P < .0001).

Similarly, the patients’ FEV₁ was lower in both the CR protocol (82% vs. 101%; P = .003) and the FD protocol (80% vs. 99%; P = .018). Airway resistance also appeared higher among patients with asthma than the control group in the CR protocol (0.51 vs. 0.33 kPa/L/second; P = .008) and the FD protocol (0.53 vs. 0.35 kPa/L/second; P = .036).

During the CR protocol, Scheer and colleagues noted that changes in the circadian system were highly significantly associated with poorer pulmonary function during the biological night, equivalent to 11 p.m. and 11 a.m., with the poorest function occurring around 4 a.m.

“This finding suggests that the circadian variation in pulmonary function would contribute to nocturnal worsening of asthma, including the worsening asthma severity before bedtime and upon awakening in the morning that was revealed by the scheduled measurements in the ambulatory data,” the researchers wrote.

Also, the timing of rescue inhaler use during the FD protocol appeared to have a significant circadian rhythm, with use four times more likely to occur during the biological night than day (81% vs. 19%; P = .03).

Researchers noted the circadian system, sleep and other behavioral and environmental effects had an additive influence on asthma, and those with the lowest average pulmonary function also had the largest daily circadian variation and behavioral cycle effects on asthma.

The study’s limitations included the small number of participants, which limited assessment on characteristics such as age and sex; repeated measurements only using noninvasive techniques; and the use of the interrupter technique to measure airway resistance, which is not thoroughly validated in adults.

The researchers concluded that, after controlling for external and behavioral factors such as sleep position and physical activity, the remaining underlying endogenous mechanisms that could contribute to the circadian rhythmicity in asthma severity include circadian variation in autonomic nervous system activity; humoral factors such as epinephrine, histamine, corticosteroids and melatonin; and airway inflammation.

“Our study helps to provide the critical foundation needed for the optimization of asthma therapy by exploiting knowledge of internal body clock time, so-called ‘circadian precision medicine,’” the researchers wrote.