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Saturday, March 23, 2024

Why Does Asthma Get Worse at Night?

In 1698, British doctor John Floyer wrote a treatise on asthma, the first major work focused on the disease. Not all of it aged well. He warned that those who were sad or angry were more likely to experience attacks, as sadness would stop the “Motion of Humors.” He also recommended a few cures including regular, gentle vomiting.

In an asthma attack, the air passageways in a person’s lungs start to close, making it hard for them to breathe and causing tightness in the chest, coughing, and wheezing. But Floyer’s piece also noted another important symptom: His own asthma was almost always more severe at night, sometimes waking him up at 1 or 2 in the morning. Hundreds of years later, scientists were finding evidence that backed him up: A study from 2005 showed that nearly 75 percent of people with asthma experience worse attacks at night. A famous mortality survey of London hospitals in the 1970s showed that early morning and nighttime attacks were more likely to be fatal.

Yet no one is sure why asthma gets worse at night, says Steven Shea, director of the Oregon Institute of Occupational Health Sciences at Oregon Health and Science University. "Most people sleep at night, so maybe it’s the sleep that causes your asthma to get worse at night," he says. Or it may be caused by body position or mites or allergens in the bedding. Or, Shea adds, “maybe it’s the internal body clock.”

That body clock is also called the circadian system. Among other important functions, it regulates hormones, heartbeat, and the immune system over a cycle that lasts about 24 hours. While this system is internal, it’s heavily influenced by outside factors like light and dark, mealtimes, and work schedules.

Historically, it’s been impossible to isolate the role of the circadian system from people’s behavior and environmental risks “because they go hand in hand,” says Frank Scheer, director of the Medical Chronobiology Program at Brigham and Women’s Hospital. “You cannot know what is actually driving changes in pulmonary function.” But in a paper published this month in Proceedings of the National Academy of Sciences, a team led by Scheer and Shea finally found a way to divorce the circadian system from all the external factors that might contribute to asthma.

First, they had their 17 study participants, all of whom had previously been diagnosed with asthma, track their pulmonary function at home during their daily lives. Four times a day, the participants used a handheld spirometer to test how much air they could push out of their lungs in one second, a measurement called FEV1. (The more, the better.) They also recorded their symptoms and noted when they had to use their rescue inhalers.

Then, things got significantly more involved. The same set of participants were put through two different experiments while living in dimly lit rooms at the Center for Critical Inquiry at Brigham and Women’s Hospital. In one experiment, called the “constant routine protocol,” participants sat in bed for 38 hours without being allowed to sleep. They couldn’t get up to use the bathroom or do any strenuous activities. Every two hours, they ate the same snack, a small peanut butter and jelly or tuna fish sandwich. They were allowed to listen to books on tape, chat with the nurses, or play card games, but they couldn’t move around or get excited or angry.

In these rooms without clocks or windows, and with the subjects no longer tied to their daily work or home schedules, external time felt like it didn’t exist. The participants had no idea when the sun rose or set, when it might be time for lunch, or when they should fall asleep.

“The constant routine protocol is based on the concept that you remove any 24-hour rhythmicity and any factors, environmental or behavioral, that may induce changes in physiology,” says Scheer.

Participants were hooked up to thermometers that monitored their core temperatures almost continuously. Every two to four hours, nurses collected blood and urine samples, took FEV1 metrics, and also measured airway resistance, which indicates if swelling or mucus buildup are making it harder to move air through the lungs. This gave the researchers a way to follow along as the circadian rhythm regulated the rise and fall of hormone levels and pulmonary function—without influence from behavioral or environmental cues.

But they also wanted to understand how behavioral cycles like sleeping or eating might affect asthma, too. So they ran another phase of the experiment called the “forced desynchrony protocol.” This time, the 17 participants had to live in those dim light conditions for eight days. But these were not normal days. Instead of living on a 24-hour cycle, all their activities—like sleeping, showering, and eating—were scheduled on a 28-hour cycle. This forced their behaviors out of sync with their circadian rhythms, “meaning that you will be able to dissociate the influence of the behavioral cycle from the central circadian control,” says Scheer. They were allowed to get up and move around a bit more than in the constant routine protocol, but they couldn’t go outside or do any strenuous exercise. Every two to four hours, they were also tested for airway resistance and FEV1.

Across all three experiments, the researchers found that a person’s circadian rhythm contributes to worsening asthma. During the circadian night, when people’s internal clocks perceived it was time to sleep, participants were four times more likely to use their inhalers. Participants who had the most pronounced increases in lung function during their circadian day also had the greatest drop in FEV1 and the greatest increase in airway resistance during their circadian night. The researchers also found that when sleep coincided with the circadian night, airway resistance  increased.

Shea says these sophisticated protocols allowed them to finally conclude that circadian rhythms do affect asthma, independent of other behavior, no matter whether people are asleep or awake. But he also adds that behaviors can still affect the severity and frequency of attacks—because unless you’re in a highly controlled lab environment, the circadian clock is never working alone. It’s always going to be affected by light, sleep cycles, mealtimes, exercise, and work. “The circadian clock is ticking away all of the time, but we’re doing things all of the time as well, and you really need to know how they add up,” he says.

Very few labs in the world have the ability to run experiments like this, says David Ray, a professor of endocrinology at Oxford University who studies the circadian system but was not involved in this study. “They were able to really clearly show that it’s the endogenous circadian system driving this,” he says. That answers a big, basic question and allows the field to move forward toward possible therapies. “This identifies new pathways that might suggest new ways to treat asthma,” Ray says.

Garret FitzGerald, a professor of translational medicine at the University of Pennsylvania who also studies molecular clocks, says this new data could inform when people use drugs like bronchodilators, or when they decide to exercise or do other activities that could exacerbate their asthma. It could even open a new avenue for drugs currently in development that could modify the circadian rhythm by shifting when people’s bodies move through different phases, or by changing the amplitude of those shifts. “This work highlights the value of small, carefully conducted studies,” he wrote in an email to WIRED, though he adds that larger clinical trials are needed, too.

It’s not exactly clear how the circadian system worsens asthma, though Scheer and Shea have a few hypotheses. One hormone that’s heavily regulated by the circadian system is cortisol, most famous for being triggered by stress. Levels drop at night but surge in the morning, ushering more glucose into the bloodstream to prepare the body for the day’s activities. “The rise in cortisol may be involved in the improvement of pulmonary function in the circadian morning,” says Scheer. Then, at night, as cortisol drains out of the system, lung function might decrease too.

Another hormonal factor could be melatonin; it rises as we get sleepier and could contribute to inflammation in the lungs. Or it could be that nighttime asthma is worsened by the autonomic nervous system, which controls involuntary movements like heartbeat and the contraction or dilation of blood vessels, and is also tied to the circadian cycle.

It’s also not clear whether a link to asthma lies in the brain’s suprachiasmatic nucleus, the region that controls circadian rhythm, or within the timekeeping apparatus of individual cells. “It’s also been shown that lung cells contain autonomous molecular clocks,” says Scheer. “So the question is whether those peripheral clocks may also be involved in regulating pulmonary function.”

Without understanding which mechanisms are involved, the researchers acknowledge that it will be a long time before this work can inform treatment. But they say it does illustrate a central paradox in helping people with asthma: Doctors rarely see it at its worst, because they don’t see patients at night. “In medicine, we are really missing an important part of the daily cycle for our diagnosis,” says Scheer.

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