SickKids study identifies potential predictor for developing cystic fibrosis for children with an inconclusive diagnosis

A diagnosis can be worrying for families, but for some, it can be a source of comfort, with a more defined pathway for a child’s medical journey. In many provinces, early diagnosis of cystic fibrosis (CF) happens through newborn screening programs. Some infants may be diagnosed with Cystic Fibrosis Screen Positive Inconclusive Diagnosis (CFSPID), indicating a baby has a positive newborn screening result, but does not meet all criteria for a CF diagnosis. However, little is known about the long-term health outcomes of children with CFSPID, and whether there is a way to predict if these children will develop CF later in life.

Children with CF often experience symptoms affecting their lungs and digestive system, including trouble breathing, slow weight gain and repeated lung infections. For those with an inconclusive diagnosis, they may not experience any symptoms or may develop symptoms later in life.

A national multi-centre study led by The Hospital for Sick Children (SickKids) followed 115 infant children with CFSPID from across Canada until school age, comparing them with children diagnosed through CF newborn screening programs, and found that almost a quarter of children with CFSPID are at risk of receiving a CF diagnosis later in childhood. The study, published in Pediatrics, showed for the first time that the initial sweat test used in newborn screening programs could also be used as a potential biomarker to predict risk of developing CF.

The research team, led by Dr. Tanja Gonska, Senior Associate Scientist, Translational Medicine and Staff Physician in Gastroenterology, Hepatology and Nutrition, followed study participants for over a decade to monitor health outcomes and conversions to a CF diagnosis. They found that lung function and nutrition of children with CFSPID was comparable to healthy children without CF. However, the team also found that children with CFSPID who had an elevated sweat test at birth above 40 mmol/L (millimoles per liter) had a 10-times higher chance of receiving a CF diagnosis as they age.

How CFPSID is diagnosed among newborns

During newborn screening, infants are screened for CF by testing for a chemical made by the pancreas called immunoreactive trypsinogen (IRT). Babies with a high IRT level will then receive a genetic test that looks for the genes responsible for causing CF (mutations found in the Cystic Fibrosis Transmembrane Conductance Regulator, or CFTR gene). A high or positive screening result prompts a sweat test, considered the gold standard for CF diagnosis, which tests the amount of chloride (salt) present in a baby’s sweat. CF is the most common cause of an elevated sweat chloride level, and levels greater than 60 mmol/L lead to a diagnosis of CF.

A provisional CFSPID diagnosis occurs when infants have sweat test results that fall within an intermediate range of 30 to 60 mmol/L and have fewer than two CFTR gene variants, or have normal sweat chloride results and two gene variants, one of which has unknown or unclear CF-causing consequences. In Canada, about one in 3,600 children are diagnosed with CF and an estimated one in every 10,000 to 15,000 babies per year are diagnosed with CFSPID but this number may increase with the use of more advanced genetic analysis during newborn screening.

“Our study showed that a cystic fibrosis diagnosis was established in 21 per cent of patients during clinical follow-up, based on an increase in sweat chloride levels to over 60 millimoles per liter or reinterpretation of gene variants,” says Gonska, who also manages the Gastroenterology-Cystic Fibrosis Clinic at SickKids. “The findings suggest an opportunity for us to better focus clinical care on patients who may have a higher risk of developing cystic fibrosis and reduce the gap of uncertainty and burden placed on families without a diagnosis.”

Though further study is needed, the researchers note that for those participants who received a CF diagnosis based on re-interpretation of gene variants, the risk of converting to a CF diagnosis might be predicted by a high initial IRT result in cases where the outcome of the follow-up genetic test is not known, as high IRT is associated with sweat conversion.

Sub-classifying patients for better risk assessment

The population study included participants from across the country, splitting them into three diagnostic groups, including patients with CFSPID, patients with pancreatic insufficient CF, and patients with pancreatic sufficient CF, who typically experience milder symptoms. Pancreatic insufficiency is the most common gastrointestinal complication of CF and can affect how nutrients from food are absorbed by the body.

Dr. Mark Chilvers, one of the paper’s authors and a paediatric respirologist and Clinic Director of the Cystic Fibrosis Clinic at BC Children’s Hospital, notes this is the first study that compares these sub-types of CF patients to children with CFPSID, giving researchers better insight into clinical presentations of CF as well as a more accurate risk assessment of children with CFSPID.

“While we show that children with CFSPID have good nutritional and pulmonary outcomes at school age, rates of reclassifying the diagnosis are relatively high,” says Chilvers. “If we could better use the diagnostic tools we already have, like the sweat test, we can potentially improve the clinical management and care of these children at a younger age or before they experience symptoms. This could help clinicians to better counsel patients and families for whom diagnostic uncertainty can be incredibly stressful.”

The team will continue to follow the participants into adulthood and say they are interested to examine whether the initial sweat test can also be used to predict those at risk for other CFTR-related diseases.