J.E. Dankert-Roelse

Clinical scores for acute asthma in pre-school children. A review of the literature

The objective of this paper was to evaluate the applicability in research and clinical practice of clinical scores for acute asthma in pre-school children. All instruments were reviewed according to a standardized set of criteria: purpose of the score, suitability for use in children, inter-observer agreement, validity and responsiveness. A Medline literature research resulted in 16 different clinical asthma scores, which have been developed to assess the severity of acute asthma, to predict the outcome of an attack, or to evaluate the response to treatment. Most asthma scores could be easily obtained in children. Three scores have been modified to facilitate application in a younger age-category. Inter-observer agreement has received little attention, although all scores contained items that require subjective judgement. The predictive validity was insufficient to justify the application of clinical scores as a decision rule for the admission or discharge of children with acute asthma. Asthma scores seem to be useful for assessing the severity of an attack and evaluating the response to therapy, but as yet there is insufficient information on the performance of the scores to justify a preference. Wheezing and retractions appear to be important items of any useful score for acute asthma.

Novel strategies in newborn screening for cystic fibrosis: A prospective controlled study

Context Newborn screening for cystic fibrosis (CF) is included in many routine programmes but current strategies have considerable drawbacks, such as false-positive tests, equivocal diagnosis and detection of carriers. Objective To assess the test performance of two newborn screening strategies for CF. Design, setting and participants In 2008 and 2009, CF screening was added to the routine screening programme as a prospective study in part of the Netherlands. Interventions Two strategies were performed in all newborns. In the first strategy, concentrations of immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP) were measured. In the second method, samples with IRT ≥60 μg/litre were analysed for 36 CFTR mutations, followed by sequencing when a single mutation was detected. Tests were positive only with two identified CFTR mutations. Main outcome Sensitivity, specificity and positive predictive value (PPV) of both screening strategies. Results 145 499 infants were screened. The IRT/PAP approach showed a sensitivity of 95.0%, a specificity of 99.897% and a PPV of 12.3%. Test properties for the IRT/DNA/sequencing strategy were respectively 100%, 100% and 64.9%. Combining both strategies (IRT/PAP/DNA/sequencing) led to a sensitivity of 95.0%, a specificity of 100% and a PPV of 87.5%. Conclusion In conclusion, all strategies performed well. Although there was no statistically significant difference in test performance, the IRT/DNA/sequencing strategy detected one infant that was missed by IRT/PAP (/DNA/sequencing). IRT/PAP may be the optimal choice if the use of DNA technology must be avoided. If identification of carriers and equivocal diagnosis is considered an important disadvantage, IRT/PAP/DNA/sequencing may be the best choice.

Cost-effectiveness of 4 neonatal screening strategies for cystic fibrosis.

OBJECTIVES. The purpose of this work was to assess the costs of 4 neonatal screening strategies for cystic fibrosis in relation to health effects. In each strategy, the first test was the measurement of serum concentration of immunoreactive trypsin. The second step consisted of either a second immunoreactive trypsin test (strategy 1) or a multiple mutation analysis (strategy 2). In strategies 3 and 4, a third step was added to strategy 2: a second immunoreactive trypsin test (strategy 3) or an extended mutation analysis of the cystic fibrosis gene, that is, a denaturing gradient gel electrophoresis analysis (strategy 4). METHODS. We conducted an economic-modeling exercise in the Netherlands based on published data and expert opinions. Subjects were a hypothetical cohort of 200 000 neonates, the approximate number of children born annually in the Netherlands, and we assessed the costs and number of life-years gained as a result of neonatal screening for cystic fibrosis. The costs and effects of changes in reproductive decisions because of neonatal screening were also assessed. RESULTS. Immunoreactive trypsin + immunoreactive trypsin had the most favorable cost-effectiveness ratio of €24800 per life-year gained. Immunoreactive trypsin + DNA + denaturing gradient gel electrophoresis achieved more health effects than immunoreactive trypsin + DNA + immunoreactive trypsin at lower cost. The incremental costs per life-year gained of the immunoreactive trypsin + DNA + denaturing gradient gel electrophoresis strategy compared with the immunoreactive trypsin + immunoreactive trypsin strategy were €130700, whereas the incremental costs of the immunoreactive trypsin + DNA strategy compared with the immunoreactive trypsin + DNA + denaturing gradient gel electrophoresis strategy were €2154300. When changes in reproductive decisions as a result of neonatal screening are also taken into account, neonatal screening for cystic fibrosis may lead to financial savings of approximately €1.8 million annually, depending on the screening strategy used. CONCLUSIONS. Cystic fibrosis screening for neonates is a good economic option, and positive health effects can also be expected. Immunoreactive trypsin + immunoreactive trypsin and immunoreactive trypsin + DNA + denaturing gradient gel electrophoresis are the most cost-effective strategies.

Screening for Cystic Fibrosis — Time to Change Our Position?

Cystic fibrosis is one of the most common inheritable diseases among white people, and without treatment most patients with this disease die in infancy or early childhood. The steadily increasing s...

CFTR mutations in Turkish and North African cystic fibrosis patients in Europe: implications for screening.

AIMS To obtain more insight into the variability of the CFTR mutations found in immigrant cystic fibrosis (CF) patients who are living in Europe now, and to estimate the test sensitivity of different frequently used methods of DNA analysis to detect CF carriers or patients among these Turkish or North African immigrants. METHODS A survey among 373 European CF centers asking which CFTR mutations had been found in Turkish and North African CF patients. RESULTS 31 and 26 different mutations were reported in Turkish and North African patients, identifying 64.2% (113/176) and 87.4% (118/135) alleles, respectively (p < 0.001). The mean sensitivity (detection rate) of three most common CFTR mutation panels to detect these mutations differed between Turkish and North African people, 44.9% (79/176) versus 69.6% (94/135) (p < 0.001), and can be increased to 57.4% (101/176) and 79.3% (107/135) (p < 0.001), respectively, by expanding these panels with 13 mutations which have been found on two or more alleles. CONCLUSION 35.8% and 12.6%, respectively, of CF alleles in Turkish and North African patients living in Europe now had not been identified. Among these populations, the test sensitivity of common CFTR mutation panels is insufficient for use in screening programs in Europe, even after expansion with frequent Turkish and North African mutations. This raises questions about whether and how to implement CF carrier and neonatal screening in a multiethnic society.

Cost-effectiveness of newborn screening for cystic fibrosis determined with real-life data

BACKGROUND Previous cost-effectiveness studies using data from the literature showed that newborn screening for cystic fibrosis (NBSCF) is a good economic option with positive health effects and longer survival. METHODS We used primary data to compare cost-effectiveness of four screening strategies for NBSCF, i.e. immunoreactive trypsinogen-testing followed by pancreatitis-associated protein-testing (IRT-PAP), IRT-DNA, IRT-DNA-sequencing, and IRT-PAP-DNA-sequencing, each compared to no-screening. A previously developed decision analysis model for NBSCF was fed with model parameters mainly based on a study evaluating two novel screening strategies among 145,499 newborns in The Netherlands. RESULTS The four screening strategies had cost-effectiveness ratios varying from €23,600 to €29,200 per life-year gained. IRT-PAP had the most favourable cost-effectiveness ratio. Additional life-years can be gained by IRT-DNA but against higher costs. When treatment costs reduce with 5% due to early diagnosis, screening will lead to financial savings. CONCLUSION NBSCF is as an economically justifiable public health initiative. Of the four strategies tested IRT-PAP is the most economic and this finding should be included in any decision making model, when considering implementation of newborn screening for CF.

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

BACKGROUND Newborn 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. METHODS Questionnaires were sent to key workers in each European country. RESULTS In 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. CONCLUSIONS There has been a steady increase in national CF NBS programmes across Europe with variable strategies and outcomes that reflect the different approaches.

Extended gene analysis can increase specificity of neonatal screening for cystic fibrosis.

Aim: To assess whether carriers and patients can be accurately identified by extended gene analysis for cystic fibrosis (CF) in dried blood spots. Methods: A blinded analysis was performed in 10‐mm2 blood spots on Guthrie cards, punched as if to remove material for the IRT test, from 10 CF patients and 10 carriers with known CF mutations. Genomic DNA was isolated. Aliquots of 1 µl dissolved DNA were used for subsequent PCRs. Analysis of the ?F508 mutation was followed by an oligonucleotide ligation assay. Denaturing gradient gel electrophoresis of the whole CFTR gene was carried out in samples with only one identified mutation. Amplicons revealing an aberrant pattern were sequenced. Results: In all cases, the blood‐spot genotype was identical to that previously determined from whole‐blood analysis. Estimated time needed to complete the procedure in a series of Guthrie cards was 3–4 wk.

Improving test properties for neonatal cystic fibrosis screening in the Netherlands before the nationwide start by May 1st 2011

When new technical possibilities arise in health care, often attunement is needed between different actors from the perspectives of research, health care providers, patients, ethics and policy. For cystic fibrosis (CF) such a process of attunement in the Netherlands started in a committee of the Health Council on neonatal screening in 2005. In the balancing of pros and cons according to Wilson and Jungner criteria, the advantages for the CF patient were considered clear, even though CF remains a severe health problem with treatment. Nevertheless, screening was not started then, mainly since the specificity of the tests available at that time was considered too low. Many healthy infants would have been referred for sweat testing and much uncertainty would arise in their parents. Also the limited sensitivity for immigrants and the detection of less severe phenotypes and carriers were considered problematic. The Health Council recommended a pilot screening project which was subsequently performed in some provinces, leading to a 4-step protocol: IRT, PAP, screening for a CFTR mutation panel, and sequencing of the CFTR gene. This would lead to the identification of 23 cases of classical CF, two infants with less severe forms and 12 carriers per year in the Netherlands. Thus many CF patients can be diagnosed early, while limiting the number of referrals, the number of infants with less severe forms diagnosed and the number of carriers identified. Technical solutions were found to limit the ethical problems. A nationwide program using this four step protocol started by 1 May 2011.

Pros and Cons of Neonatal Screening for Cystic Fibrosis

In the past, several experimental schemes for neonatal screening for the presence of Cystic Fibrosis have been tried out. Several benefits of early detection have been claimed, but few studies are methodologically flawless, mainly because of the use of historical controls and/or a too short period of follow-up. At least initially, many programs suffered from the fact that after detection no systematic patient treatment scheme was available, and that no consensus was available on optimal treatment. The life expectancy of patients with cystic fibrosis has considerably improved over the last decades, mainly because better antibiotics became available and because treatment of complications has improved.