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.     

Lung transplantation in cystic fibrosis patients in the Czech Republic: initial single-center experience

Background

Lung transplantation is a well established treatment for advanced lung diseases.

Methods

We compared the clinical results of patients with cystic fibrosis (CF) entered into the waiting list with those of patients after lung transplantation.

Results

Among 36 patients with CF on the waiting list, 23 underwent lung transplantation, 8 died, 3 are still on the waiting list, and 2 were excluded from the waiting list. The median waiting list time of 0.48 years (range, 0.03-2.37) was insignificantly longer for patients who died compared with transplanted patients (0.97 vs 0.44 years). Mortality of waiting-list patients was 25.8%. The median survival of transplant patients of 7.48 years (range 0.00-10.85 years) was significantly lower among patients who were colonized (BCC) versus those who were not Burkholderia cepacia complex (0.19 vs 7.48 years; P = .041). The 1-, 3-, and 5-year patient survivals after lung transplantation were 72.9, 54.4, and 54.4, respectively.

Conclusion

The results of patients with cystic fibrosis on the waiting list versus after lung transplantation in our center were similar to those reported in the literature. We confirmed a less favorable prognosis of BCC-colonized patients.     

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.     

A survey of newborn screening for cystic fibrosis in Europe.

BACKGROUND: Cystic fibrosis (CF) is a recessively inherited condition caused by mutation of the CFTR gene. Newborn infants with CF have raised levels of immuno-reactive trypsinogen (IRT) in their serum. Measurement of IRT in the first week of life has enabled CF to be incorporated into existing newborn screening (NBS) blood spot protocols. However, IRT is not a specific test for CF and NBS therefore requires a further tier of tests to avoid unnecessary referral for diagnostic testing. Following identification of the CFTR gene, DNA analysis for common CF-associated mutations has been increasingly used as a second tier test. The aim of this study was to survey the current practice of CF NBS programmes in Europe. METHOD: A questionnaire was sent to 26 regional and national CF NBS programmes in Europe. RESULTS: All programmes responded. The programmes varied in number of infants screened and in the protocols employed, ranging from sweat testing all infants with a raised first IRT to protocols with up to four tiers of testing. Three different assays for IRT were used; in the majority (24) this was a commercially available kit (Delfia). A number of programmes employed a second IRT measurement in the 4th week of life (as the IRT is more specific at this point). Nineteen programmes used DNA analysis for common CFTR mutations on samples with a raised first IRT. Three programmes used a second IRT measurement on infants with just one recognised mutation to reduce the number of infants referred for sweat testing. Referral to clinical services was prompt and diagnosis was confirmed by sweat testing, even in infants with two recognised mutations in most programmes. Subsequent clinical pathways were less uniform. Multivariate analysis demonstrated a relationship between the age of diagnosis and the timing of the first IRT. More sweat tests were undertaken if the first IRT was earlier and the diagnosis was later. CONCLUSIONS: Annually these programmes screen approximately 1,600,000 newborns for CF and over 400 affected infants are recognised. The findings of this survey will guide the development of European evidence based guidelines and may help new regions or nations in the development and implementation of NBS for cystic fibrosis.     

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.

A European consensus for the evaluation and management of infants with an equivocal diagnosis following newborn screening for cystic fibrosis

Screening newborns for cystic fibrosis (CF) is considered to be an ethical undertaking in regions with a significant incidence of the condition. Current screening protocols result in recognition of infants with an equivocal diagnosis. A survey of European practice suggested inconsistencies in the evaluation and management of these infants.We have undertaken a consensus process using a modified Delphi method. This has enabled input of CF specialists from a wide geographical area to a rigorous process that has provided a clear pathway to a consensus statement. A core group produced 21 statements, which were modified over a series of three rounds (including a meeting arranged at the European CF Conference). A final document of 19 statements was produced, all of which achieved a satisfactory level of consensus. The statements cover four themes; sweat testing, further assessments and investigations, review arrangements and database.This consensus document will provide guidance to CF specialists with established screening programmes and those who are in the process of implementing newborn screening in their region.     

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.     

Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening

BackgroundSuccessful implementation of newborn screening (NBS) for cystic fibrosis (CF) depends on robust protocols, good communication and appropriate management of recognised infants. In response to current varied practice, the ECFS Neonatal Screening Working Group developed a consensus on the early management of these infants using the Delphi methodology.MethodsFollowing detailed literature review, statements were generated by a core group of experts and then assessed by a larger group using modified Delphi methodology.ResultsForty-one statements were written by the core group. Eighty-six CF specialists contributed to the modified Delphi process. During three rounds, extra statements were added and consensus achieved on 44 (one statement did not achieve consensus).ConclusionsThese statements will provide a framework for the management of screened infants in the first year of life. This process highlights the paucity of evidence on which to base management of these infants. To improve this situation, it is important that each infant with CF identified through NBS has opportunity to be included in a randomised controlled trial.     

A nationwide blood spot screening study for Fabry disease in the Czech Republic haemodialysis patient population.

BACKGROUND: Fabry disease (FD) is a genetic disorder characterized by accumulation of trihexosylceramide in lysosomes of various tissues leading to multiorgan manifestations, including progressive renal disease. Previous screening studies have shown that a non-neglectable proportion of haemodialysis(HD) patients have unsuspected FD. An extensive FD screening study, the largest to date, has been conducted in HD patients in Czech Republic. We aimed to uncover previously undiagnosed FD patients, to enable them to benefit from cause-specific therapeutic intervention with enzyme replacement therapy (ERT). METHODS: Large-scale screening was executed using a convenient automated enzymatic (alpha-galactosidose A, alpha-Gal A) dried blood spot on filter paper fluorescence method. RESULTS: In total, 3370 (45.1% males, 54.9% females) out of 4058 HD patients (83%) in Czech Republic participated in this blood spot screening (BSS) study. Abnormal low fluorescence readings were obtained in 117 patients (3.5%). Subsequent determination of plasma alpha-Gal A activity identified four males and three females with deficient plasma enzyme activity. Determination of alpha-Gal A activity in peripheral blood leucocytes and confirmatory molecular analysis resulted in four newly diagnosed Fabry males and one female. Subsequent family screening identified 10 family members with genotypically proven FD. Based on these screening results, ERT could be offered to five male FD patients. CONCLUSIONS: BSS represents a promising screening tool that has proven to be convenient and effective in uncovering unrecognized FD patients among the chronic HD population in Czech Republic.     

Pilot study on the use of acoustic radiation force impulse imaging in the staging of cystic fibrosis associated liver disease

BackgroundAcoustic radiation force impulse (ARFI) is a novel technique for the measurement of hepatic stiffness, which could be valuable in clinical follow-up of patients affected by cystic fibrosis liver disease (CFLD).MethodsSeventy-five patients with suspected CFLD (35 males) underwent clinical and ultrasonographic evaluations, liver and pulmonary function tests, ARFI investigation, and upper gastrointestinal endoscopy. Ten ARFI measurements were taken at the deep right hepatic lobe to compute median values of Shear Wave Velocity (SWV) for each individual.ResultsSWV increased progressively from 1.02 m/s (95%, Confidence Interval, CI, 0.92–1.126) in patients with no evidence of CFLD at ultrasonography (N = 16), to 1.12 (95%CI 1.049–1.19) in patients with CFLD and no signs of portal hypertension (PHT, N = 23), and to 1.25 (95%CI 1.14–1.358) in those with CFLD and signs of PHT (N = 28). SWV was 1.63 (95%CI 1.26–1.99) in patients with oesophageal varices (N = 8) (p < 0.0001).ConclusionsARFI may represent an easy, fast and non-invasive tool for the clinical follow-up of patients with cystic fibrosis associated liver disease.