Newborns With Unclear CF Tests May Develop Disease Later

Diedtra Henderson

May 13, 2015

Eleven percent of infants who had inconclusive results for cystic fibrosis (CF) as newborns went on to develop the disease by age 3 years, underscoring the need for additional tests by skilled clinicians, including monitoring of sweat chloride and searching for disease-causing mutations, according to a prospective longitudinal study.

The study, by Chee Y. Ooi, MBBS, PhD, from the Discipline of Pediatrics, School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, Australia, and colleagues, is one of two articles published online May 11 in Pediatrics that examine how to care for children who are CF screen positive but receive an inconclusive diagnosis (CF screen positive inconclusive diagnosis; CFSPID).

CF is a genetic disorder that shortens the lifespan of up to 1 in 2500 white infants and results in sticky mucus gumming up the body's organs and air passages, according to the National Institutes of Health.

Dr Ooi and colleagues enrolled 162 newborns from June 2007 to August 2013 from seven CF clinics in Canada and Italy. Eighty-two infants were found to have CFSPID at newborn testing, and 80 had CF.

The last clinical review was conducted at a median age of 24.8 months for the CF cohort and 24 months for the CFSPID cohort.

"Nine of 82 (11%) subjects with CFSPID fulfilled the diagnostic criteria for CF during the follow-up period on the basis of genotype and/or abnormal sweat chloride (≥60 mmol/L)," Dr Ooi and colleagues write. "[Four] (4.9%) subjects were diagnosed on the basis of genotype alone, 3 (3.7%) on the basis of both genotype and abnormal sweat chloride, and 2 (2.4%) on the basis of abnormal sweat chloride only."

The authors note that during the follow-up period, Pseudomonas aeruginosa was isolated in 12% of those patients with CFSPID and Stenotrophomonas maltophilia was isolated in 5% of the children with CFSPID.

In addition, sweat chloride became elevated at a mean age of 21.3 months in the children who were switched from a CFSPID to a CF diagnosis. Those children also had significantly higher serial sweat chloride (P < .0001) and serum trypsinogen (P = .009) levels than did the children whose diagnosis remained CFSPID.

Because the infants diagnosed by sweat testing were 21.3 months old at the time sweat chloride increased, the authors suggest that repeat sweat testing also be done when infants are 2 or 3 years old. At this time, the US Cystic Fibrosis Foundation recommends repeat sweat testing at age 6 months for infants with an equivocal diagnosis.

"[Newborn screening]-positive infants with an inconclusive diagnosis of CF are not uncommon. These children are at risk of positive cultures for CF-associated bacteria as well as fulfilling the diagnostic criteria of CF over time and thus require monitoring, ideally by CF clinicians," Dr Ooi and coauthors conclude.

In a second study, Clement L. Ren, MD, from the Division of Pediatric Pulmonology, Department of Pediatrics, University of Rochester, New York, and colleagues analyzed data from the US CF Foundation Patient Registry from 2010 to 2012. The researchers compared demographic and clinical data for infants with CF and infants with cystic fibrosis transmembrane conductance regulator–related metabolic syndrome (CRMS). Similar to infants with a CFSPID diagnosis, those with CRMS have a positive CF newborn screen but inconclusive diagnostic testing for CF and are asymptomatic.

On the basis of the CF Foundation guideline definitions, the researchers identified 1540 infants who met the criteria for CF and 309 infants who met the criteria for CRMS (CF:CRMS ratio = 5.0:1.0).

The infants with CRMS were more likely to be black, Asian, Native American, or mixed race. In general, they had normal growth and nutrition, but "concerning" laboratory tests. In addition, these infants were "significantly less likely" to be prescribed CF treatment, Dr Ren and colleagues write, with just 7.8% receiving pancreatic enzyme replacement therapy compared with 76.2% of the 1540 infants diagnosed with CF.

At least one respiratory culture positive for Pseudomonas aeruginosa was recorded in 10.7% of infants with CRMS compared with 20.9% of infants with CF (P < .05).

"CRMS is a common outcome arising from CF [newborn screening], and although the vast majority of infants with CRMS are healthy, a small proportion of them may develop manifestations of CF," Dr Ren and coauthors conclude.

Cystic Fibrosis Canada provided financial support for the first study. Its authors have disclosed no relevant financial relationships. The Cystic Fibrosis Foundation provided financial support for the second study. Three coauthors disclosed being employees of the Cystic Fibrosis Foundation, and a fourth coauthor disclosed receiving grants and personal fees from CFF. The four remaining coauthors have disclosed no relevant financial relationships.

Pediatrics. Published online May 11, 2015. Ooi abstract, Ren abstract


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