The expansion and performance of national newborn screening programmes for cystic fibrosis in Europe

BackgroundNewborn screening (NBS) for cystic fibrosis (CF) is a well-established public health strategy with international standards. The aim of this study was to provide an update on NBS for CF in Europe and assess performance against the standards.MethodsQuestionnaires were sent to key workers in each European country.ResultsIn 2016, there were 17 national programmes, 4 countries with regional programmes and 25 countries not screening in Europe. All national programmes employed different protocols, with IRT-DNA the most common strategy. Five countries were not using DNA analysis. In addition, the processing and structure of programmes varied considerably. Most programmes were achieving the ECFS standards with respect to timeliness, but were less successful with respect to sensitivity and specificity.ConclusionsThere has been a steady increase in national CF NBS programmes across Europe with variable strategies and outcomes that reflect the different approaches.     

Opportunities for quality improvement in cystic fibrosis newborn screening

BackgroundWith the rapid implementation of cystic fibrosis (CF) newborn screening (NBS), quality improvement (QI) has become essential to identify and prevent errors. Using Process Failure Modes and Effects Analysis (PFMEA), we adapted this method to determine if it could be applied to discover and rank high priority QI opportunities.MethodsSite visits to three programmes were conducted, and PFMEA exercises were accomplished in Colorado, Massachusetts and Wisconsin with 23 experienced professionals. During each of these comprehensive sessions, participants identified and ranked potential failures based on severity, occurrence and detection to calculate risk priority number (RPN) values.ResultsA total of 96 failure modes were generated and ranked in a list of the 20 riskiest problems that show no significant discordances by site, although there were differences by profession of the rater, particularly nurses.ConclusionsOur results illustrate that the PFMEA method applies well to CF NBS and that steps requiring communication and information transfer are perceived to be the highest risks. The number of identified failures makes and their potential impact demonstrate considerable overall risk and a need for ongoing QI.     

Cost effectiveness of newborn screening for cystic fibrosis: A simulation study

BackgroundEarly detection of cystic fibrosis (CF) by newborn screening (NBS) reduces the rate of avoidable complications. NBS protocols vary by jurisdiction and the cost effectiveness of these different protocols is debated.ObjectiveTo compare the cost effectiveness of various CF NBS options.MethodsA Markov model was built to simulate the cost effectiveness of various CF-NBS options for a hypothetical CF-NBS program over a 5-year time horizon assuming its integration into an existing universal NBS program. NBS simulated options were based on a combination of tests between the two commonly used immunoreactive trypsinogen (IRT) cutoffs (96th percentile and 99.5th percentile) as first tier tests, and, as a second tier test, either a second IRT, pancreatic-associated protein (PAP) or CFTR mutation panels. CFTR mutation panels were also considered as an eventual third tier test. Data input parameters used were retrieved from a thorough literature search. Outcomes considered were the direct costs borne by the Quebec public health care system and the number of cases of CF detected through each strategy, including the absence of screening option.ResultsIRT–PAP with an IRT cutoff at the 96th percentile is the most favorable option with a ratio of CAD$28,432 per CF case detected. The next most favorable alternative is the IRT1–IRT2 option with an IRT1 cutoff at the 96th percentile. The no-screening option is dominated by all NBS screening protocols considered. Results were robust in sensitivity analyses.ConclusionThis study suggests that NBS for cystic fibrosis is a cost-effective strategy compared to the absence of NBS. The IRT–PAP newborn screening algorithm with an IRT cutoff at the 96th percentile is the most cost effective NBS approach for Quebec.     

Reclassifying inconclusive diagnosis after newborn screening for cystic fibrosis. Moving forward

BackgroundNewborn screening for Cystic Fibrosis (CF) is associated with situations where the diagnosis of CF or CFTR related disorders (CFTR-RD) cannot be clearly ruled out.Materials/patients and methodsWe report a case series of 23 children with unconclusive diagnosis after newborn screening for CF and a mean follow-up of 7.7 years (4–13). Comprehensive investigations including whole CFTR gene sequencing, in vivo intestinal current measurement (ICM), nasal potential difference (NPD), and in vitro functional studies of variants of unknown significance, helped to reclassify the patients.ResultsExtensive genetic testing identified, in trans with a CF causing mutation, variants with varying clinical consequences and 3 variants of unknown significance (VUS). Eighteen deep intronic variants were identified by deep resequencing of the whole CFTR gene in 13 patients and were finally considered as non-pathogenic. All patients had normal CFTR dependent chloride transport in ICM. NPD differentiated 3 different profiles: CF-like tracings qualifying the patients as CF, such as F508del/D1152H patients; normal responses, suggesting an extremely low likelihood of developing a CFTR-RD such as F508del/TG11T5 patients; partial CFTR dysfunction above 20% of the normal, highlighting a remaining risk of developing CFTR-RD such as F508del/F1052V patients. The 3 VUS were reclassified as variant with defective maturation (D537N), defective expression (T582I) or with no clinical consequence (M952T).ConclusionThis study demonstrates the usefulness of combining genetic and functional investigations to assess the possibility of evolving to CF or CFTR-RD in babies with inconclusive diagnosis at neonatal screening.     

Mental Health screening in cystic fibrosis centres across Europe

Objectives

The Cystic Fibrosis (CF) International Mental Health Guidelines Committee published consensus statements for screening and treating depression and anxiety in individuals with CF and their caregivers. This work aimed to evaluate the dissemination and implementation of the guidelines in Europe two years following their publication.

Strategies for newborn screening for cystic fibrosis: A systematic review of health economic evaluations

Background

Early detection of cystic fibrosis through newborn screening has significant clinical benefits. Cost-effectiveness plays an important role in selecting the optimal screening strategy from the many available options.

Bronchiectasis in an asymptomatic infant with cystic fibrosis diagnosed following newborn screening

Many countries have introduced newborn screening for cystic fibrosis to facilitate diagnosis prior to the development of lung disease. Although most infants with cystic fibrosis are asymptomatic from a respiratory point of view at diagnosis, structural lung disease has been detected by computed tomography. We present a case of an asymptomatic infant with cystic fibrosis diagnosed following newborn screening who had endobronchial infection with Pseudomonas aeruginosa and radiological evidence of bronchiectasis at 3 months of age.     

Insights into the cystic fibrosis care in Eastern Europe: Results of survey

Background

The European cystic fibrosis (CF) Society Standards of Care were set to facilitate the delivery of high-quality care throughout Europe. However, their implementation may be difficult for less economically advantaged countries. This survey was performed to explore the gap in the knowledge of the level of CF care in Eastern Europe.

Pulmonary outcome differences in U.S. and French cystic fibrosis cohorts diagnosed through newborn screening

BackgroundA comparison of the longitudinal progression of lung disease in cystic fibrosis patients identified through newborn screening (NBS) in cohorts located in two different countries has never been performed and was the primary objective of this study.MethodsThe study included 56 patients in Brittany diagnosed through NBS between 1989 and 1994 and 69 similar patients in Wisconsin between 1985 and 1994. The onset and progression of lung disease was radiographically quantified using the Wisconsin Chest X-ray (WCXR) scoring system. A single pediatric pulmonologist blinded to all identifiers scored the films.ResultsGeneralized estimating equation analyses adjusted for age, genotype, sex, pancreatic insufficiency, and meconium ileus showed worse WCXR scores in Brittany patients compared to Wisconsin patients (average score difference = 4.48; p < 0.001). Percent predicted FEV1 was also worse among Brittany patients (p < 0.001).ConclusionsThe finding of milder radiographically-quantified lung disease using the WCXR scoring system, as well as better FEV1 values, may be explained by variations in nutrition, environmental exposures, or healthcare delivery.     

Cystic fibrosis newborn screening does not delay the identification of cystic fibrosis in children with negative results

Background

Several studies have demonstrated the benefit of Cystic Fibrosis Newborn Screening (CFNBS) for early diagnosis and, hence, intervention but the impact of CFNBS on those children not detected on CFNBS is not known. CFNBS may provide false reassurance that all CF has been detected and, therefore, lead to a delay in the diagnosis of children with CF which is not detected on CFNBS. The aim of this study was to determine the impact of CFNBS on the presenting features of children with CF where CF was not detected on CFNBS.

Methods

Subjects at the CFNBS center were selected if CF was identified subsequent to a negative CFNBS with subjects at the No CFNBS selected based on the absence of ΔF508 mutations. Children presenting with features that would lead to investigation for CF independent of clinical status were excluded. Presenting features at diagnosis and pulmonary function at 6 years of age were extracted from medical records.

Results

Twelve children from the CFNBS site and 19 from the No CFNBS site were included in the analysis. The only significant difference between the two in features at diagnosis was lower mean weight z-scores at the No CFNBS site (− 2.9 ± 1.8) compared to the CFNBS center (− 1.4 ± 1.3, p < 0.05). Age at diagnosis, presenting complaint and nutritional status did not differ by site. Growth parameters and pulmonary function at 6 years of age showed no differences between sites.

Conclusions

This study demonstrates that access to CFNBS does not result in delay in diagnosis or poorer outcomes in those children for whom CF was not detected on CFNBS. In addition, children with CF not detected on CFNBS present with typical features of CF and sweat chloride results that are diagnostic of CF.