Diagnosis and screening<< Back to Clinical management of CF
Click on the tabs to move through the sequence.
The ‘standard’ and internationally accepted test for CF is the sweat test. However, with over 1700 CFTR mutations giving rise to a wide range of clinical symptoms, there is increasing use of genetic analysis in the diagnosis and screening of CF. Thus, both genetic and physiological tests are included in current diagnostic algorithms for CF.1
The sweat test is often considered the ‘gold standard’ for the diagnosis of CF and is based on a standardised test introduced by Gibson–Cooke in 1959.2,8 Over the years there has been some controversy concerning the definition of borderline levels of sweat chloride. Original guidelines suggested a borderline sweat chloride of 40–59 mmol/L; however, recent European guidelines specify a range of 30‒59 mmol/L.1,3
It is worth noting that although American CF guidelines currently stipulate a borderline range of 40–59 mmol/L, a comparison of both US and European guidelines showed general concordance in diagnostic outcomes among subjects with single-organ manifestations of CF.4
CF diagnosis using the sweat test is based on the patient having one or more characteristic feature(s) of CF and evidence of a CFTR abnormality based on one of the following:5
- Two abnormal sweat chloride values (≥60 mmol/L); and/or
- Presence of two disease-causing mutations in the CFTR gene
CF newborn screening is routinely practised in many European countries6 and is mainly based on the detection of elevated levels of immunoreactive trypsinogen (IRT) in the newborn’s blood. A positive test is usually followed by DNA testing to identify known CFTR gene mutations (IRT/DNA strategy) or it may be repeated when the infant is approximately 2 weeks old (IRT/IRT strategy).7
Some reports suggest that the IRT/DNA strategy could be replaced by an easier and more cost-effective screening test; namely, measurement of pancreatic-associated protein (PAP) and IRT.8
European Cystic Fibrosis Society recommended diagnostic algorithm for CF.9
Genetic testing, or CFTR genotyping, has transformed CF care. The majority of patients in Western Europe have been genetically screened; for example, in the UK and France around 95%11 and 94%12 of CF sufferers have already been genotyped. Furthermore, with advances in therapies that target specific CFTR defects, it is very likely that genotyping will become an integral part of CF diagnosis.
The current clinical applications for CFTR genetic testing are:
- Carrier testing – This is advocated in relatives of a person with CF or in the partner of a CF carrier who is planning to have children. Carrier couples may also be identified through investigations for foetal bowel anomalies.12
- Newborn screening (NBS) programmes – Routine NBS programmes have been implemented throughout most of Western Europe and currently account for about 59% of European infants.6 Nevertheless, there is definite need for expansion and harmonisation of such programmes in Europe.12 [Click on the Newborn Screening tab to discover more].
- Prenatal screening (PNS) of high-risk pregnancies – PNS should be offered to parents diagnosed with CF where both parental mutations have been identified. The test should only be performed with parental consensus and after genetic counselling.
- Establish or confirm a CF diagnosis – With over 1500 CFTR mutations13 reported and extensive heterogeneity in the distribution of CFTR gene mutations across Europe,14 it is challenging to achieve a mutation detection rate >95%.15
Nasal potential difference (NPD) is a measurement of the voltage across the nasal epithelium obtained by placing an electrode on the nasal passages. The magnitude of the voltage potential is influenced by the transport ions, such as sodium and chloride, across cell membranes. Individuals with CF have a more negative baseline potential difference compared with those who do not have CF.
As the NPD is technically challenging to perform its use is restricted to only a few specialised CF centres where it is mainly used as a research tool.