Updated screening protocols could improve early diagnosis of cystic fibrosis

All states should adopt updated screening protocols so more newborns with cystic fibrosis can be diagnosed in the first weeks of life, when interventions can have the greatest benefit, according to the Cystic Fibrosis Foundation guidelines published April 2 in the International Journal of Neonatal Screening. 

Current newborn screening protocols vary across states. Some states use outdated protocols that often miss cases of the inherited disease, especially in newborns with Black, Hispanic and Asian, as well as American Indian and multiracial ancestry, said Dr. Meghan McGarry, a pediatric lung specialist and associate professor of pediatrics at the University of Washington School of Medicine. 

McGarry and Karen Siklosi Raraig, assistant professor of genetic medicine, Johns Hopkins University, were the co-lead authors of the guidelines. 

Because the disease impairs the newborn’s ability to absorb nutrients, a delay in diagnosis of a week or so can lead to damaging weight loss and other complications. If the diagnosis is missed, you will often see serious growth problems and permanent lung damage as the child grows older.”

Dr. Meghan McGarry, pediatric lung specialist and associate professor of pediatrics, University of Washington School of Medicine

Cystic fibrosis is an inherited disorder that affects about 40,000 children and adults in the United States. It occurs when a child inherits two mutated copies of a certain gene, one from each parent. This gene normally provides instructions for the synthesis of a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), which controls the movement of salt and water in and out of cells. 

Mutations that prevent the synthesis of this protein, or that produce abnormal versions of the protein, can have a profound effect on the function of cells that produce mucous, sweat and other secretions. They can make mucous and secretions thick and gluey, and make sweat extra salty. The thickened secretions can block and damage secreting glands and allow infections to occur, particularly in the lungs. 

People with cystic fibrosis can develop endocrine, gastrointestinal, pancreatic, liver and reproductive disorders, but lung disease is often the most common complication and the principal cause of death. With early diagnosis and new treatments, life expectancy of people with cystic fibrosis has improved greatly in recent years, but many still succumb in their 40s.

Currently, all U.S. newborns are screened for cystic fibrosis. This is done by collecting a few drops of blood from a heel prick. The blood is tested for a protein called immunoreactive trypsinogen (IRT), which tends to run high in newborns with cystic fibrosis. If the IRT level is elevated, another sample of blood is collected to screen the newborn’s DNA for mutations in the CFTR gene. If mutations are identified, additional tests will be done to confirm the diagnosis. 

Although all states test for IRT, McGarry said, they differ on what levels are considered an abnormal finding. This disparity causes some cystic fibrosis cases to be missed. States also differ in the number of mutations they screen for. Although more than 1,000 mutations are now known to cause cystic fibrosis, some states test for only one mutation, and others for only 40. Limited DNA tests can miss many cases to be missed, particularly in newborns with rarer mutations that are found more in Asian, Hispanic, Black, American Indian and multiracial babies, the guideline authors note.

The Cystic Fibrosis Foundation’s new guidelines call for uniform screening protocols in all states. They also recommend that IRT screening labs should be run twice a week to preclude delays in diagnosis, and that IRT screens use metrics that account for factors like temperature and humidity, which can affect results. The guidelines also state that when IRT levels are elevated, laboratories should screen for all mutations known to cause cystic fibrosis. 

The guideline writers also note that a positive test finding is not necessarily a formal diagnosis, nor does a negative test mean the child does not have cystic fibrosis. 

“If a baby presents with signs and symptoms of cystic fibrosis, pediatricians should not rule out cystic fibrosis solely on the basis of their normal newborn screening,” McGarry said. “Families have faced difficulties getting further testing, despite the baby showing classic signs of cystic fibrosis, based on a normal initial screen.” 

Currently, a formal diagnosis is made with a relatively simple test that measures the chloride content of a person’s sweat. 

“Newborn screening should be updated and standardized so that it benefits all families equally,” McGarry said. “All babies deserve early diagnosis and early treatment so they can have the best outcomes.” 

The guidelines appear in the DATE issue of the International Journal of Neonatal Screening. Marci Sontag, director of the Center for Public Health Innovation, and Dr. Susanna McColley, professor of pediatrics at the Northwestern University Feinberg School of Medicine in Chicago, were the senior authors of the guidelines.