Cystic Fibrosis Diagnosis in Newborns, Children, and Adults

Carlo Castellani, MD; Barry Linnane, MB, BCh, BAO, DCH, MRCPI, MRCPCH, MD; Iwona Pranke, PhD; Federico Cresta, MD; Isabelle Sermet-Gaudelus, MD, PhD; Daniel Peckham, MD


Semin Respir Crit Care Med. 2019;40(6):701-714. 

In This Article

Inconclusive Diagnosis Following CF NBS

Both genetic analysis and sweat test may give inconclusive diagnostic results: the clinical liability of the identified mutations can be variable or unknown and the sweat chloride levels in the intermediate range. Also the clinical assessment may be non-informative. In such situations the suspected diagnosis of CF can neither be confirmed nor excluded.

These events are inherent in any NBS program, but more frequent if non-mutation-specific genetic assays, like sequencing, are used as a post-IRT tier. In this regard, some algorithms may lead to the identification of as many newborns with inconclusive diagnosis as CF infants,[112] while protocols avoiding the use of genetic analysis or including only panels of CF causing mutations usually limit their detection.[113–115]


In the United States, these unresolved cases are defined as "CF transmembrane conductance regulator (CFTR)-related metabolic syndrome" (CRMS),[116] in Europe as "CF screen positive, inconclusive diagnosis" (CFSPID).[117] The minor differences between the definitions of CRMS and CFSPID were resolved by a consensus meeting convened in 2015 by the US Cystic Fibrosis Foundation, which accomplished a harmonization of the two terms.[95] These infants are now defined as CRMS/CFSPID if they present positive NBS results (i.e., a neonatal IRT value above the cut-off chosen by the established protocol) plus:

  • Sweat chloride below 30 mmol/L and two CFTR mutations of which 0–1 annotated as CF causing by the CFTR2 program,[118] or

  • Sweat chloride between 30 and 59 mmol/L and less than two CFTR mutations annotated as CF causing by the CFTR2 program.[95,118]

In spite of the current availability of a clear definition of these NBS-originated situations, several pediatric pneumologists and CF-specialists seem not to interpret it properly. A recent survey by the NBS Working Group of the European CF Society (ECFS) showed that a significant percentage of these professionals deliver incorrect diagnostic interpretations of these situations, highlighting the need of more education activities targeting CF health workers.[119]


The individual clinical outcome of newborns with CRMS/CFSPID is not predictable.

A significant percentage of the CFTR sequence variations detected in CRMS/CFSPID infants are found also in single organ CFTR-related disorder (CFTR-RD). These include congenital bilateral absence of the vas deferens, chronic or acute recurrent pancreatitis, and disseminated bronchiectasis, and, like CRMS/CFSPID cases, have intermediate or normal sweat chlorides values.[120] This coincidence and the raised IRT levels at birth indicate that children with CRMS/CFSPID may have an increased risk to develop CFTR-RD or even CF.

Evidence so far collected suggests that most of these infants will not have developed systemic symptoms or have been diagnosed with CF by 3 years of age.[95] However, several of them have over time had airway cultures positive for P. aeruginosa and Staphylococcus aureus,[121,122] an event more likely in infants with initial intermediate sweat chloride values.[95]

Long-term studies of large cohorts are needed to define better the possible correlations between CRMS/CFSPID, CF and CFTR-RD and the long-term trend of these infants.


In the light of the unpredictable clinic development, a regular follow-up of these infants at a CF center is recommended.[117] These visits may involve a substantial cost for the health system and an increase in the workload for CF-clinics, particularly if the local NBS strategy detects high numbers of these infants. Segregation rules and separate clinics should be arranged and contact with CF patients avoided. The clinical history since the last contact should be collected, with particular attention to events compatible with CF. Each visit should include a throat swab culture, whereas sweat tests should be performed less frequently. The emergence of a phenotype consistent with CFTR-RD or CF and/or a repeatedly positive sweat test will allow a specific diagnosis. In the absence of evocative clinical manifestations or significant increase of sweat chloride values, it is still unclear for how long these children should be followed.

Families have to be informed about the possibility of health issues, and in particular of the increased risk of respiratory illness and should be aware of the importance of maintaining a healthy lifestyle, even if the child is eventually discharged from routine controls.[123] If two CFTR mutations are detected, parents should be offered genetic counseling. Although a CRMS/CFSPID diagnosis appears to be associated with lower familial anxiety levels than CF diagnosis, the poorly predictable clinical evolution represents a source of considerable concern for the parents.[124]