Five-year study aims to improve health of patients with cystic fibrosis across their growing lifespan

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People with cystic fibrosis are living better and longer, and now investigators want to further enhance quality and longevity by better understanding the role of nutrition, body composition and exercise in their health across an increasing lifespan.

While CF may be viewed primarily as a lung disease, the abnormally thick mucus that clogs patients’ airways also obstructs other fundamentals like digesting food and absorbing nutrients, producing sufficient insulin, sleeping and exercising, says Dr. Ryan A. Harris, clinical exercise and vascular physiologist at the Georgia Prevention Institute at the Medical College of Georgia at Augusta University.

Harris is principal investigator on a new five-year longitudinal phenotyping study assessing these divergent, non-pulmonary aspects of the disease, how they interact and identifying barriers to healthy habits like regular exercise.

MCG is enrolling 50 patients age 6 and older in the five-year study funded by the National Institutes of Health. Emory University is also enrolling 50 patients in the study as part of the new collaborative between Emory, MCG at AU and Georgia Tech that established the Georgia Cystic Fibrosis Research and Translation Core Center. The new center has as its focus nonpulmonary aspects of CF and Emory was awarded a $1.7 million grant from the NIH to support the collaborative. Harris is the AU PI and the PI of the overall center’s Lifestyle and Behaviors Core.

AU and Emory are home to the only two Cystic Fibrosis Foundation-accredited care centers in Georgia and among 130 nationally. Dr. Kathleen McKie, interim chief of the Division of Pediatric Pulmonology in the MCG Department of Pediatrics, is the center’s pediatric program director, and Dr. Caralee J. Forseen, adult pulmonologist in the MCG Department of Medicine, is the adult program director. McKie and Forseen codirect the CF Center at AU and are coinvestigators on Harris’ new study.

A key problem with CF is mutations in the gene that produce the cystic fibrosis transmembrane conductance regulator protein. That protein typically forms a channel on the cell surface to enable chloride — a component of salt — to move in and out of cells. When the protein doesn’t get made or doesn’t get made correctly, chloride can become trapped inside cells so it can’t attract the fluids needed to hydrate the cells’ surface and the mucus that lines the surface of places like the lungs and gastrointestinal tract becomes thick and dysfunctional.

“The thick mucus is everywhere, they have sinus disease, GI problems, their pancreas doesn’t work properly so they don’t absorb fats and nutrients like you and I do. They have higher rates of kidney stones, higher rates of gallstones, higher rates of gastric cancer, depression, diabetes and infertility particularly in males.”

Dr. Caralee J. Forseen, Adult Pulmonologist, MCG Department of Medicine

Today’s drug therapy targets the protein problem, helps normalize mucus and improve life expectancy, but with longer life comes increased risk of other diseases like heart disease, which tend to increase with age, the investigators say.

While heart disease is the number one cause of death in Georgia and the United States, individuals with CF may be at even higher risk because of related problems like exercise intolerance as well as about a 50-50 chance of developing diabetes, aspects the center and new study are exploring.

Most often between the ages of 18-24 about half of patients with CF develop a hybrid of types 1 and 2 diabetes, called cystic fibrosis-related diabetes, or CFRD, that largely leaves them insulin dependent. The two CF centers in Georgia are working to understand at what point patients develop prediabetes and then full-blown disease and identify molecular pathways that provide insight into this transition, Harris says. They know the thick mucus is scarring the pancreas and impairing its ability to make insulin, a hormone that helps glucose enter cells where it can be used for energy or stored.

The new study should help generate information about which patients are most likely to develop CFRD, how diet and exercise might help reduce the risk and identify new directions for nutrition research.

Study participants are keeping a food diary for three days, including one weekend day, looking at the impact of diet quality on body composition and clinical outcomes with the hypothesis that a better diet will mean a higher percentage of lean body mass, increased ability to force air out of the lungs and potentially a reduced diabetes risk.

Malnutrition/malabsorption starting early in life has traditionally been a problem for patients and considered a contributor to lung disease and survival, so patients have been encouraged to eat a high-calorie, high-fat diet, which can become problematic with a longer life. Preliminary findings at MCG indicate adults with CF have a low quality diet as measured by the United States Department of Agriculture’s Healthy Eating Index, including consuming a lot of sugar, which is associated with visceral adiposity, fat in the abdominal area and another major risk factor for heart disease and diabetes, and a higher fasting glucose level than those without the disease.

Particularly as patients live longer, it’s important to identify the optimal diet for maintaining optimal health, Harris says. So they are asking patients about their gastrointestinal function and also keeping an eye on liver function through ultrasound and lab tests.

“In the past it was high-calorie, high-protein, whatever kind of calories you can get in,” Forseen says, because of problems with absorbing fats and needed nutrients. Now some adult and pediatric patients taking the newer treatment struggle with gaining too much weight, McKie notes. While her patients who are still too young to take Trikafta, the latest iteration of the protein modulator therapy, still struggle to take in sufficient calories and nutrition.

To further assess physical activity and barriers to it, investigators are doing fitness tests including, a six-minute self-paced walk to see how far patients can go with vital signs monitored as they walk. Maximal exercise capacity is being assessed using a cycle ergometer, a stationary bike that measures how much physical work the rider is doing, as they keep tabs on key effort indicators like oxygen saturation and blood pressure.

They also are measuring grip strength and lower body power fitness. Periodic pulmonary function tests will assess lung function over time to identify any changes, and investigators will be keeping up with levels of nitric oxide exhaled because higher levels indicate the body is fighting lung inflammation, a hallmark of CF. Investigators will be assessing arterial stiffness, because stiff arteries are a risk factor for heart disease, and exercise combats arterial stiffness.

Study participants also will wear an accelerometer, which measures the vibration of motion, to keep track of movement and sleep quality. Sleep is key to overall health, so the investigators want to know how people with CF sleep and how much the coughing often associated with the disease interferes.

They also want to know if those who exercise daily have better outcomes and they have early evidence that, like in the general population, they do. In fact, there are studies indicating exercise capacity is an independent predictor of mortality in patients with CF, Harris says.

Still there does not seem to be the expected connection between lung health and exercise capacity in these patients.

“We are really trying to understand why patients with CF have exercise intolerance because it is not directly related to their lung health,” Harris says. Blood vessels are not necessarily smaller, or clogged up in CF, they are just not as compliant and as efficient at perfusing muscle and organs, he says. There may be dysfunction with the small blood vessels, or microcirculation, directly connected to the muscle that is connected to the skeleton that moves our bodies, and there appears to be skeletal muscle dysfunction as well, Harris says.

Forseen, a big exercise advocate, says exercise has the added benefit of helping clear the airway in CF, and McKie notes the long collaboration with exercise physiologist Harris has already helped make exercise a priority for patients at the Augusta center.

They also are looking at the related role of body composition and fat distribution on lung function and glucose tolerance, an indicator of diabetes risk, over time. They want to determine the role of physical activity in body composition and clinical outcomes with the hypothesis that, like what happens in most of us, more activity translates to improvements in lean body mass, lung function and glucose tolerance, while patients who are inactive will lose ground in these important health indicators.

Many of us can increase lean body mass with steps like avoiding fatty foods, foods high in sugar and weight training. But patients with CF are known to have difficulty maintaining lean body mass, like muscle, another difficulty associated with increased risk of death from their disease.

CF can create a vicious cycle where the lack of lean body mass as well as reduced lung function can impair the ability to exercise, Harris says. And, whether exercise will really help improve lean body mass in these patients is unclear because the reasons behind their deficit also is unclear, he says.

“We know they have better lung outcomes if their BMI is at the target, which is the 50th percentile,” McKie says.

The two CF experts characterize the therapy that addresses underlying causes of CF as game changers for their patients. The CF Foundation says that people born with CF between 2015-19 have a life expectancy of 46 years, and Forseen now has some patients in their 70s. The Food and Drug Administration recently announced it will make a decision on whether to expand Trikafta to 6-11 year olds by this June.

“Patients are living longer and leading more normal lives,” says Forseen, probably 15 years longer than when she joined the MCG faculty in 2005 after completing a pulmonary/critical care fellowship at the University of Texas Southwestern. McKie, a 2001 MCG graduate who joined the faculty in 2006, concurs on the dramatic improvements.

“Now we are seeing people going to work who were never able to hold a job, getting advanced degrees, getting married, having children, they are living a normal life that they thought they could have,” Forseen says. “I think our goal now is to continue to improve that quality of life.”

Harris and McKie reported in 2012 the first evidence of blood vessel dysfunction and exercise intolerance in a small group of patients with CF who were generally healthy. Their findings, published in CHEST Journal, indicated an impaired ability for blood vessels to dilate when exercise or stress increases their body’s need for blood and oxygen. Their oxygen saturation was lower at rest than their healthy counterparts, and their bodies were generally less efficient at using oxygen during exercise.

The apparent first heart attack in a patient with CF was reported in the Journal of the Royal Society of Medicine in a 48-year-old white male. The investigators speculated then that the high-fat diet patients are encouraged to eat and the higher incidence of diabetes would increase heart attack risk in patients who were living longer. Four years earlier, there was the first report of a patient with CF diagnosed with symptomatic heart disease in the journal BMC Pulmonary Medicine.

Patients at the Cystic Fibrosis Center at AU were part of the evaluation of the newer, game-changing modulator therapies. “One of my prior colleagues said there would never be a cure for CF, and it won’t be long before he is wrong and I am very happy,” Forseen says.

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