Devil in the detail of newborn screening for cystic fibrosis

Doull, Iolo

doi:10.1136/archdischild-2018-316247

Cited by 6 publications

(6 citation statements)

References 17 publications

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“…CFSPID is a common problem occurring with mutation analysis-based CF screening strategies. This has led to the widespread view that the individual’s phenotype rather than an equivocal genotype should be treated [ 27 ]. On the other hand, taking into account the successful reduction of CF rates by effective carrier screening strategies [ 28 ], a lack of carrier detection could also be regarded as disadvantageous depending on ethics varying from country to country.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, taking into account the successful reduction of CF rates by effective carrier screening strategies [ 28 ], a lack of carrier detection could also be regarded as disadvantageous depending on ethics varying from country to country. Patients with CFSPID may benefit from detection by NBS [ 29 ], although uncertainty remains challenging for families and caregivers and strategies for the follow-up of these patients are not commonly established yet [ 27 ]. Several European countries do not use DNA testing for CF screening [ 30 ], and neonatal genetic screening is often not adequately addressed in European laws [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

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Cystic Fibrosis Newborn Screening in Austria Using PAP and the Numeric Product of PAP and IRT Concentrations as Second-Tier Parameters

Zeyda

Schanzer

Basek³

et al. 2021

Diagnostics

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In Austria, newborns have been screened for cystic fibrosis (CF) by analyzing immunoreactive trypsinogen (IRT) from dried blood spots (DBS)s for nearly 20 years. Recently, pancreatitis-associated protein (PAP) analysis was introduced as a second-tier test with the aim of reducing recalls for second DBS cards while keeping sensitivity high. For 28 months, when IRT was elevated (65-130 ng/ml), PAP was measured from the first DBS (n = 198,927) with a two-step cut-off applied. For the last 12 months of the observation period (n = 85,421), an additional IRT×PAP cut-off was introduced. If PAP or IRT×PAP were above cut-off, a second card was analyzed for IRT and in case of elevated values identified as screen-positive. Above 130 ng/mL IRT in the first DBS, newborns were classified as screen-positive. IRT analysis of first DBS resulted in 1,961 (1%) tests for PAP. In the first 16 months, 26 of 93 screen-positive were confirmed to have CF. Two false-negatives have been reported (sensitivity = 92.8%). Importantly, less than 30% of families compared to the previous IRT-IRT screening scheme had to be contacted causing distress. Adding IRT×PAP caused a marginally increased number of second cards and sweat tests to be requested during this period (15 and 3, respectively) compared to the initial IRT-PAP scheme. One case of confirmed CF was found due to IRT×PAP, demonstrating an increase in sensitivity. Thus, the relatively simple and economical algorithm presented here performs effectively and may be a useful model for inclusion of CF into NBS panels or modification of existing schemes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cystic Fibrosis Newborn Screening in Austria Using PAP and the Numeric Product of PAP and IRT Concentrations as Second-Tier Parameters

Zeyda

Schanzer

Basek³

et al. 2021

Diagnostics

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“…The use of additional biomarkers such as pancreatitis-associated protein (PAP) in conjunction with IRT can improve specificity but has only minimal impact on sensitivity [23][24][25]. Alternatively, the extension of CFTR molecular testing to include more expansive panels or full gene sequencing cannot address the initial sensitivity issues with IRT and has the unfavorable effect of enriching for CFSPID cases [22,26].…”

Section: False Negativesmentioning

confidence: 99%

Performance of a Three-Tier (IRT-DNA-IRT) Cystic Fibrosis Screening Algorithm in British Columbia

Sinclair

McMahon

Schellenberg

et al. 2020

IJNS

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Newborn screening for Cystic Fibrosis has been implemented in most programs worldwide, but the approach used varies, including combinations of immunoreactive trypsinogen (IRT) and CFTR mutation analysis on one or more specimens. The British Columbia (BC) newborn screening program tests ~45,000 infants per year in BC and the Yukon Territory, covering almost 1.5 million km2 in western Canada. CF screening was initiated using an IRT-DNA-IRT approach with a second bloodspot card at 21 days of age for all CFTR mutation heterozygotes and any non-carriers in the top 0.1% for IRT. This second IRT was implemented to avoid sweat testing of infants without persistent hypertrypsinemia, reducing the burden of travel for families. Over nine years (2010–2018), 401,977 infants were screened and CF was confirmed in 76, and a further 28 were deemed CF screen positive inconclusive diagnosis (CFSPID). Day 21 IRT was normal in 880 CFTR mutation carriers who were quoted a very low CF risk and offered optional sweat testing. Only 13% of families opted for sweat testing and a total of 1036 sweat tests were avoided. There were six false negative CF cases (and three CFSPID) due to a low initial IRT or no CFTR mutations. Although one CFSPID case had a normal repeat IRT result, the addition of the day 21 IRT did not contribute to any CF false negatives.

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“…CF is an autosomal recessive disorder caused by one of more than 2,000 variants in the gene encoding the CF transmembrane conductance regulator (CFTR) anion channel. As such, newborn screening is now being widely implemented to diagnose children shortly after birth [2]. While multiple organs are affected in patients with CF, the majority of morbidity and mortality is due to airway disease [3].…”

Section: Introductionmentioning

confidence: 99%

Pilot study of inflammatory biomarkers in matched induced sputum and bronchoalveolar lavage from 2-year-olds with cystic fibrosis

Giacalone

Giraldo

Margaroli

et al. 2022

Preprint

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Background: In this pilot study, we investigated whether induced sputum (IS) could serve as a viable alternative to bronchoalveolar lavage (BAL) and yield robust inflammatory biomarkers in toddlers with cystic fibrosis (CF) featuring minimal structural lung disease. Methods: We collected IS, BAL (right middle lobe and lingula) and blood, and performed chest computed tomography (CT) scans from 2-year-olds with CF (N=11), all within a single visit. Inflammatory biomarkers included 20 soluble immune mediators and neutrophil elastase (NE), as well as frequency and phenotype of T cells, monocytes / macrophages and neutrophils. Results: At the molecular level, nine mediators showed similar levels in IS and BAL (CXCL1, CXCL8, IL-1, IL-1RA, IL-6, CCL2, CXCL10, M-CSF, VEGF-A), four were higher in IS than in BAL (CXCL5, IL-1, CXCL11, TNFSF10) and two were present in IS but undetectable in BAL (IL-10, IFN-). Meanwhile, soluble NE had lower activity in IS than in BAL. At the cellular level, T-cell frequency was lower in IS than in BAL. Monocytes / macrophages were dominant in IS and BAL with similar frequencies but differing expression of CD16 (lower in IS), CD115 and surface-associated NE (higher in IS). Neutrophil frequency and phenotype did not differ between IS and BAL. Conclusions: IS collected from 2-year-olds with CF yields biomarkers of early airway inflammation with good agreement with BAL notably with regards to molecular and cellular outcomes related to neutrophils and monocytes/macrophages.

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Devil in the detail of newborn screening for cystic fibrosis

Cited by 6 publications

References 17 publications

Cystic Fibrosis Newborn Screening in Austria Using PAP and the Numeric Product of PAP and IRT Concentrations as Second-Tier Parameters

Cystic Fibrosis Newborn Screening in Austria Using PAP and the Numeric Product of PAP and IRT Concentrations as Second-Tier Parameters

Performance of a Three-Tier (IRT-DNA-IRT) Cystic Fibrosis Screening Algorithm in British Columbia

Pilot study of inflammatory biomarkers in matched induced sputum and bronchoalveolar lavage from 2-year-olds with cystic fibrosis

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