Early lung problems in children with CF tied to genetics, environment

Evidence justifies increasing effort toward reducing risk tied to extrinsic factors

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A doctor examines a child who's sitting on his mother's lap.

Both genetics and environmental factors, such as attending daycare, family income, and maternal education, may determine how early some lung problems develop in children with cystic fibrosis (CF), a study finds.

This is important because while variations in a person’s genes can’t be modified, “some extrinsic exposures can and should become targets for interventions,” its researchers wrote in “Impact of intrinsic and extrinsic risk factors on early-onset lung disease in cystic fibrosis,” which was published in Pediatric Pulmonology.

Children with CF often develop lung problems early in life. The mucus in their airways becomes thick and sticky, making it difficult to breathe, resulting in frequent lung infections and other symptoms.

Using a scoring system they developed called CF Early-onset Lung Disease (CFELD), the researchers found that about half of children with the disease may already show signs of lung problems by age 3.

These problems may manifest early due to a number of genetic and environmental factors working in combination, and the researchers believe that “environmental factors are at least as important as genetic predisposition.”

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CF and genetic makeup

To test this, they looked at 104 children born from 2012 to 2017 who were diagnosed with CF by the time they were 3 months and were followed until they turned 3 years as part of the FIRST study, which took place in five pediatric CF centers in the U.S.

How lung problems manifested at each visit were noted and the researchers used this information to calculate the CFELD score, which ranged in severity from asymptomatic, meaning no symptoms at all (0), to minimal (1-2), mild (3-4), moderate (5-8), and severe (9-12).

A small proportion (6%) of children were asymptomatic. The rest had minimal (16%), mild (29%), moderate (36%), and severe (13%) lung problems.

Half the children carried two copies of F508del, the most common CF-causing mutation, and 38 (36%) had one copy of F508del and one copy of another mutation linked to pancreatic insufficiency. Six had a mutation linked to pancreatic insufficiency other than F508del. Pancreatic insufficiency occurs when the pancreas doesn’t release enough enzymes to break down food in the intestines, causing digestive symptoms. In earlier work, the researchers found that pancreatic insufficiency was linked to higher CFELD scores.

Indeed, it was more common for children who had at least one copy of a mutation linked to a functioning pancreas to be asymptomatic or have minimal lung problems compared with children with mutations linked to pancreatic insufficiency.

The researchers also calculated each child’s polygenic risk score, a measure of how likely they are to develop disease based on their genetic makeup.

Children with a lower polygenic risk score, indicating worse lung function, were more likely to have moderate or severe lung problems based on their CFELD score.

Influence of environmental factors on CF

Children from families with higher and stable income, where both parents were involved and whose mothers attended at least community college were less likely to have more severe lung problems.

Better nutrition at birth, indicated by heavier and taller babies, and at age 3, indicated by taller children, was also linked to a lower risk of severe lung problems.

Children who were exposed to smoke or spent 20 hours or more a week in daycare were more likely to have more severe lung problems. Attending daycare was linked to higher chances of a pulmonary exacerbation, or symptoms getting worse.

“The early onset of CF lung disease can be attributed similarly to both genetic and nongenetic (both social and environmental) risk factors,” the researchers wrote.

Among the 52 children who carried two copies of F508del, or were homozygous, a higher polygenic risk score and a stable socioeconomic family situation were linked to lower chances of more severe lung problems. But attending daycare and being admitted to the hospital due to gastrointestinal or nutrition-related issues were linked to a higher chance of more severe lung problems.

“Our finding that these extrinsic risk factors play a significant role in the development of early-onset lung disease in F508del homozygous children provides new evidence to justify increased effort toward reducing the risk associated with these extrinsic factors,” the researchers said.