Diagnostic Tests: Sweat Testing, Epithelial Potential Differences and Genetic Testing

The diagnosis of CF is usually supported by an abnormal sweat test (chloride concentration ≥60 mmol/L) and/or the identification of two CF-causing CFTR-variants in trans (where CFTR is cystic fibrosis transmembrane conductance regulator), by using targeted tests or the in-depth analysis of the CFTR gene. However, physicians may face diagnostic challenges in cases of equivocal sweat tests (30–59 mmol/L) or if CFTR variants with variable clinical consequences or of unknown significance are identified. Problematic cases may require alternative functional tests. Nasal potential difference measurement (NPD) distinguishes CF from healthy controls, even with equivalent sweat chlorides, but is extremely challenging in infants and young children. Intestinal current measurement, that relies on ex vivo measurement of CFTR activity in rectal biopsies, discriminates pancreatic sufficient (PS)-CF from healthy individuals better than NPD and is applicable even in infants. Limitations are cost and availability. Beta-adrenergic sweat testing relies on the measurement of the amount of CFTR-stimulated sweat. It discriminates carriers from healthy controls and can diagnose PS CF with normal sweat chlorides. Intestinal organoids were also recently introduced in specialized laboratories as a promising diagnostic tool. The proper use of a combination of functional and genetic outcomes, may help to clarify equivocal diagnoses, improve patient care and offer appropriate genetic counselling to partners and relatives.