Cystic Fibrosis (CF) diagnosis has undergone significant evolution, especially with the advent of universal newborn screening and advancements in genetic testing. These changes necessitate refined diagnostic criteria to accurately identify individuals with CF and related conditions. This article delves into the essential aspects of CF diagnosis, guided by national clinical care guidelines, ensuring optimal patient care and management.
Understanding the Shifting Landscape of CF Diagnosis
The landscape of CF diagnosis has been significantly reshaped by two key factors: universal newborn screening (NBS) and the increased sophistication of CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) genetic testing. Initially, CF diagnosis relied heavily on recognizing clinical signs and symptoms combined with evidence of CFTR dysfunction. However, NBS programs now identify many newborns before symptoms manifest, requiring a different diagnostic approach. Furthermore, our enhanced understanding of CFTR gene variants allows genetic testing to play a more central role in defining CF and related disorders.
These advancements have illuminated scenarios where previous diagnostic criteria proved inadequate. A common challenge arises when newborns screen positive for CF but do not meet the traditional sweat chloride or genetic confirmation criteria. In the United States, these cases were categorized as CFTR-related metabolic syndrome (CRMS), while European experts adopted the term CF Screen Positive, Inconclusive Diagnosis (CFSPID). These terms describe the diagnostic ambiguity in infants with a positive newborn screen who don’t fully meet classic CF diagnostic benchmarks. Another related condition is CFTR-related disorder (CFTR-RD), where CFTR dysfunction contributes to specific clinical issues without fulfilling the complete criteria for a CF diagnosis.
Methodology Behind the Diagnostic Guidelines
Recognizing these evolving diagnostic complexities, the Cystic Fibrosis Foundation convened a panel of 32 CF diagnosis experts from 10 countries. This expert group was tasked with revising existing diagnostic criteria to address the challenges posed by newborn screening, genetic advancements, and ambiguous diagnostic cases. The process involved extensive discussions leading to specific consensus statements. These statements were then put to a vote among the conference participants, requiring an 80% agreement threshold for enactment. Statements falling short of this threshold underwent further refinement and iterative discussion until consensus was reached. The comprehensive outcomes of this rigorous process were subsequently published as a series of six articles in a supplementary issue of the Journal of Pediatrics, establishing updated national guidelines for CF diagnosis and clinical care.
Key Diagnostic Recommendations for Clinical Practice
The revised guidelines provide a series of crucial recommendations to standardize and enhance CF diagnosis across diverse clinical scenarios. These recommendations span various aspects of diagnostic procedures and interpretations, ensuring accurate and timely identification of CF and related conditions.
| Recommendations | Evaluation of the Evidence |
|---|---|
| 1. Sweat chloride testing should adhere to approved procedural guidelines published in established international protocols, such as the Clinical and Laboratory Standards Institute (CLSI) 2009 Guidelines. | Consensus, 100% agreement |
| 2. For newborns with a positive CF newborn screen, bilateral sweat testing is recommended to maximize specimen adequacy, ideally when the infant weighs >2 kg and is at least 36 weeks of corrected gestational age. | Consensus, 87% agreement |
| 3. Newborns older than 36 weeks gestation and >2 kg body weight with a positive CF newborn screen, or positive prenatal genetic test, should undergo sweat chloride testing as soon as possible after 10 days of age, ideally within the neonatal period (4 weeks of age). | Consensus, 93% agreement, 1 abstention |
| 4. In infants with presumptive CF identified through NBS, CF treatment initiation should not be delayed while diagnostic confirmation efforts are underway. | Consensus 83% agreement, 1 abstention |
| 5. Sweat chloride analysis should be performed promptly, within a few hours of collection, with results and interpretations communicated to clinicians and families on the same day. | Consensus, 90% agreement |
| 6. A CF diagnosis is confirmed in individuals with a positive newborn screen, clinical features consistent with CF, or a positive family history, when the sweat chloride value is ≥60 mmol/L. | Consensus, 93% agreement |
| 7. Individuals who are screen-positive and meet sweat chloride criteria for CF diagnosis should undergo CFTR genetic testing if comprehensive genotype information is not already available from screening. | Consensus, 100% agreement |
| 8. In individuals with a positive newborn screen, a sweat chloride of | Consensus, 82% agreement, 2 abstentions |
| 9. A sweat chloride value less than 30 mmol/L in individuals with potential CF clinical features makes CF less likely, but it remains a consideration if clinical and/or CFTR genotyping strongly suggest CF and alternative diagnoses are excluded. | Consensus, 80% agreement |
| 10. Individuals presenting with a positive newborn screen, CF symptoms, or a positive family history, and intermediate sweat chloride values (30-59 mmol/L) on two separate occasions, may have CF and should be evaluated with extended CFTR gene analysis and/or CFTR functional analysis. | Consensus, 90% agreement |
| 11. The latest classifications from the CFTR2 project are essential for CF diagnosis: 1. CF-causing mutation: Two copies on separate alleles strongly indicate CF (sweat chloride confirmation needed). 2. Mutation of varying clinical consequence (MVCC): In combination with a CF-causing mutation or another MVCC mutation, CF may result. 3. Uncharacterized mutation/mutation of unknown clinical consequence (UNK): Disease-causing potential is unclear, requiring further evaluation. 4. Non-CF causing mutation: CF is unlikely due to this allele. | Consensus, 100% agreement |
| 12. Identification of two CF-causing mutations (as defined by CFTR2) in individuals with a positive newborn screen, CF symptoms, or a positive family history, supports a CF diagnosis, which requires sweat chloride testing for confirmation. | Consensus, 87% agreement |
| 13. Exclusion of CF diagnosis is not warranted solely based on the absence of two identified CF-causing CFTR mutations. | Consensus, 93% agreement, 1 abstention |
| 14. Advanced CF functional testing (nasal potential difference [NPD] and intestinal current measurement [ICM]) should be performed in validated reference centers with certified staff from the CF Foundation Therapeutics Development Network (TDN) or European Cystic Fibrosis Society Clinical Trial Network (CTN). | Consensus, 100% agreement |
| 15. In individuals with a positive newborn screen but variable or uncharacterized CFTR mutations (less than two CF-causing mutations), CF diagnosis can be established by demonstrating CFTR dysfunction (sweat chloride >60 mmol/L or CF-typical NPD or ICM). | Consensus, 93% agreement |
| 16. The terms CRMS (U.S.) and CFSPID (Europe) are used to describe an inconclusive diagnosis following NBS. | Consensus, 96% agreement, 2 abstentions |
| 17. CRMS/CFSPID designation is for screen-positive individuals without clinical features consistent with CF. | Consensus, 83% agreement, 1 abstention |
| 18. CRMS/CFSPID is defined as a positive NBS test for CF and either: 1. A sweat chloride value 2. An intermediate sweat chloride value (30-59 mmol/L) and one or no CF-causing mutations | Consensus, 86% agreement, 1 abstention |
| 19. Children designated as CRMS/CFSPID should undergo at least one repeat sweat chloride test at CF centers with specialized expertise, such as accredited CF centers. | Consensus, 86% agreement, 1 abstention |
| 20. Clinical evaluation by CF providers is recommended for children with CRMS/CFSPID to identify the subset who may develop clinical symptoms. | Consensus, 83% agreement, 1 abstention |
| 21. Extended CFTR gene analysis (sequencing and or deletion duplication testing) and CFTR functional analysis (NPD/ICM) can be considered for children with CRMS/CFSPID to refine their risk assessment for developing CF. | Consensus, 80% agreement |
| 22. Reclassifying CRMS/CFSPID to CF requires integrated consideration of CFTR functional assessment (sweat chloride, NPD/ICM), CFTR genetic analysis, and clinical assessment by CF clinicians. | Consensus, 90% agreement |
| 23. Genetic counseling should be offered to families of individuals followed for CRMS/CFSPID, including discussion of recurrence risk in future pregnancies. | Consensus, 100% agreement, 1 abstention |
| 24. Further research is essential to determine the prognosis and optimal follow-up strategies for infants with CRMS/CFSPID, as they lack clinical features of CF by definition. | Consensus, 96% agreement |
| 25. Diagnostic criteria for sweat chloride testing, CFTR genetic analysis, and CFTR functional testing are consistent for both screened and symptom-presenting populations. | Consensus, 95% agreement |
| 26. CFTR-related disorder is defined as a monosymptomatic clinical entity (CBAVD/pancreatitis/bronchiectasis) linked to CFTR dysfunction that does not meet full CF diagnostic criteria. | Consensus, 86% agreement, 2 abstentions |
| 27. Terms like classic/nonclassic CF, typical/atypical CF, and delayed CF should be avoided due to lack of standardized definitions and potential for family confusion. | Consensus, 83% agreement, 1 abstention |
Navigating Diagnostic Challenges and Unanswered Questions
Despite significant progress, certain diagnostic challenges and unanswered questions remain in CF clinical care. One prominent area is the long-term outcome for newborns diagnosed with CRMS/CFSPID. CF clinicians currently lack comprehensive data on the likelihood of disease progression in these individuals and the most effective strategies for identifying those at higher risk of developing CF. Consequently, there is no established consensus on the optimal follow-up and monitoring protocols for asymptomatic individuals with CRMS/CFSPID.
Caption: Illustration depicting the process of sweat chloride testing, a crucial step in diagnosing Cystic Fibrosis, especially in newborns identified through screening programs.
Furthermore, individuals presenting with isolated findings such as bronchiectasis, sinus disease, or pancreatitis pose diagnostic complexities due to a broad differential diagnosis. In cases where CF diagnosis remains inconclusive, diagnosing CFTR-RD necessitates expert clinical interpretation, particularly when sweat chloride and/or genetic testing yields indeterminate results. Clinical suspicion of CFTR dysfunction as the primary cause of symptoms is crucial in guiding diagnostic decision-making in these scenarios.
The utilization of nasal potential difference (NPD) and intestinal current measurements (ICM) outside of research settings also varies geographically, with less frequent use in the U.S. compared to Europe. As standardized protocols for these techniques are established and their diagnostic utility is further investigated, their role in CF diagnosis will become clearer, potentially enhancing diagnostic accuracy in complex cases.
Conclusion: Implementing National Guidelines for Improved CF Clinical Care
These national guidelines represent a significant step forward in standardizing and refining CF diagnosis in the era of newborn screening and advanced genetic testing. By adhering to these recommendations, healthcare professionals can ensure accurate and timely diagnoses, facilitating appropriate clinical care and management strategies for individuals with CF and CFTR-related disorders. Continuous research and clinical experience will further refine these guidelines, ultimately improving patient outcomes and quality of life for those affected by cystic fibrosis.
Further Reading
Relevant manuscripts published after the original guidelines provide further insights and are listed below.
- Farrell P, White T. Introduction to Cystic Fibrosis Foundation Consensus Guidelines for Diagnosis of Cystic Fibrosis. J Pediatr. 2017 Feb S1-3. doi: 10.1016/j.jpeds.2016.09.062.
- Farrell P, White T, Deriches N, Sastellani C, Rosenstein B. Cystic Fibrosis Diagnostic Challenges over 4 Decades: Historical Perspectives and Lessons Learned. J Pediatr. 2017 Feb;181S:S16-S26. doi: 10.1016/j.jpeds.2016.09.067.
- Sosnay P, Salinas D, White T, et al. Applying Cystic Fibrosis Transmembrane Conductance Regulator Genetics and CFTR2 Data to Facilitate Diagnosis. J Pediatr. 2017 Feb S27-32.e1. doi: 10.1016/j.jpeds.2016.09.063.
- Farrell P, White T, Howenstine M, et al. Diagnosis of Cystic Fibrosis in Screened Populations. J Pediatr. 2017 Feb S33-44e.2. doi: 10.1016/j.jpeds.2016.09.065.
- Ren C, Borowitz D, Gonska T, et al. Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome and Cystic Fibrosis Screen Positive, Inconclusive Diagnosis. J Pediatr. 2017 Feb S45-51.e1. doi: 10.1016/j.jpeds.2016.09.066.
- Sosnay P, White T, Farrell P, et al. Diagnosis of Cystic Fibrosis in Nonscreened Populations. J Pediatr. 2017 Feb S52-57.e2. doi: 10.1016/j.jpeds.2016.09.068.
