Outcomes of Cystic Fibrosis Screening–Positive Infants With Inconclusive Diagnosis at School Age

Gonska, Tanja; Keenan, Katherine; Au, Jacky; Dupuis, Annie; Chilvers, Mark; Burgess, Caroline; Bjornson, Candice; Fairservice, Lori; Brusky, Janna; Kherani, Tamizan; Jober, Amanda; Kosteniuk, Lorna; Price, April; Itterman, Jennifer; Morgan, Lenna; Mateos-Corral, Dimas; Hughes, Daniel; Donnelly, Christine; Smith, Mary Jane; Iqbal, Shaikh; Arpin, Jocelyn; Reisman, Joe; Hammel, Joanne; Wylick, Richard van; Derynck, Michael; Henderson, Natalie; Solomon, Melinda; Ratjen, Félix

doi:10.1542/peds.2021-051740

Cited by 33 publications

(36 citation statements)

References 33 publications

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“…Because we were concerned that our Phase 2 IRT/NGS algorithm including all VVCCs resulted in diagnosing more infants with CRMS/ CFSPID than infants with CF, our evaluation and improvement plan was aimed at decreasing the overall number of infants diagnosed with CRMS/CFSPID without sacrificing the potential to identify infants with CRMS/CFSPID who were at higher risk of converting to CF, that is, those who initially have sweat chloride values in the intermediate range. 37 In looking carefully at the sweat chloride values in CRMS/ CFSPID patients in Phase 2, there were 55 infants whose sweat chloride was <30 mmol/L and 21 infants whose sweat chloride was ≥30 mmol/L. Thus, Phase 3 of optimization was planned to utilize NGS for pathogenic variants only plus R117H.…”

Section: Discussionmentioning

confidence: 99%

Refinement of newborn screening for cystic fibrosis with next generation sequencing

Rock

Baker

Antos

et al. 2022

Pediatric Pulmonology

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Background Newborn screening for cystic fibrosis (CF) has been underway universally in the United States for more than a decade, as well in most European countries, and algorithms have been evolving throughout this period with quality improvement projects as immunoreactive trypsinogen (IRT) determinations alone have been transformed to a 2‐tier strategy with DNA analyses. Objective To apply next generation sequencing (NGS) as a screening method to expand the DNA tier and identify substantially more variants in the CF transmembrane conductance regulator (CFTR) gene to enhance sensitivity and equity while minimizing incidental findings. Design Sequential evaluation and improvement plan in three phases using algorithm modifications coupled to statewide follow up and analysis of screening outcomes. Results After demonstrating feasibility in the first phase, we studied an IRT/NGS algorithm that included CFTR Variants with Varying Clinical Consequences (VVCCs). This revealed a high identification of CF patients with 2‐variants detected through screening, but for every CF case there were 1.4 with CF metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID). This led us to a third phase of improvement in which the VVCCs were eliminated except for R117H, resulting in 94% 2‐variant detection of patients and 0.44:1 ratio of CRMS/CFSPID to CF. Conclusion NGS can be used with IRT as an effective method of identifying infants at risk for CF without an appreciable increase in detection of carriers. Its potential added value includes facilitating equity, enhancing sensitivity and detecting more CF patients with 2‐variants during the screening process.

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Section: Discussionmentioning

confidence: 99%

Refinement of newborn screening for cystic fibrosis with next generation sequencing

Rock

Baker

Antos

et al. 2022

Pediatric Pulmonology

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“…21 Thus, it remains unclear whether the baseline IRT measured at birth can be used as a predictor of CF reclassification. 31 Other findings included no identification of CFTR-related disorder (CFTR-RD) and no association of asthma or reactive airways disease with reclassification to CF. CFTR-RD was defined in 2011 as a diagnosis related to CFTR dysfunction that does not fulfill the diagnosis criteria for CF and typically manifests in one affected organ system (congenital bilateral absence of the vas deferens [CBAVD], pancreatitis, or bronchiectasis).…”

Section: Discussionmentioning

confidence: 99%

“…A final thought is that although currently published data showed that most children with CRMS/CFSPID designation have a favorable outcome, data is limited to a small number entered in national registries and short follow up time. 27,31,38 The short follow up may be attributed to young age of this population, early discharge per physician's decision, and high rates of lost-to-follow up. 39 The second challenge for defining prognosis in this population is high variability in duration of follow up, care practices, and CF reclassification criteria despite improved guidelines.…”

Section: Discussionmentioning

confidence: 99%

Increase in Sweat Chloride Concentration Is Associated with a Higher Risk of CFSPID to CF Reclassification

Salinas

Ginsburg

Wee

et al. 2022

Preprint

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Objectives: Universal implementation of cystic fibrosis (CF) newborn screening (NBS) has led to the diagnostic dilemma of infants with CF screen positive, inconclusive diagnosis (CFSPID), for which there is limited guidance regarding prognosis and standardized care. Rates of reclassification from CFSPID to CF vary and risk factors for reclassification are unknown. We investigated whether clinical characteristics are associated with risk of reclassification from CFSPID to a CF diagnosis. Methods: Children with a positive CF NBS were recruited from two sites in California. Retrospective, longitudinal, and cross-sectional data were collected. A subset of subjects had nasal epithelial cells collected for CFTR functional assessment. Multivariate logistic regression was used to assess the risk of CFSPID-to-CF reclassification. Results: A total of 112 children completed the study (CF=53, CFSPID=59). Phenotypic characteristics between groups showed differences in pancreatic insufficiency prevalence, immunoreactive trypsinogen (IRT) levels, and Pseudomonas aeruginosa (PSA) colonization. Spirometry measures were not different between groups. Nasal epithelial cells from 10 subjects showed 7-30% of wild type (WT)-CFTR function in those who reclassified and 27-67% of WT-CFTR function in those who retained the CFSPID designation. Modeling revealed that increasing sweat chloride concentration (sw[Cl ]) and PSA colonization were independent risk factors for reclassification to CF. Conclusion: Increasing sw[Cl ] and history of PSA colonization are associated with risk of reclassification from CFSPID to CF in a population with high IRT and two CFTR variants. Close follow-up to monitor phenotypic changes remains critical in this population. The role of CFTR functional assays in this population requires further exploration.

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“…A separate single center study found 6% of CRMS/CFSPID patients were reclassified as CF over the course of 12 years 84 . In Canada, 115 children with CRMS/CFSPID over ˜7 years were assessed, and CF was diagnosed in 21% 85 . Those infants with a SC that was [?…”

Section: Crms/cf-spidmentioning

confidence: 99%

Cystic fibrosis year in review 2021

Savant

2022

Preprint

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People with cystic fibrosis (CF) have an amazing outlook with the treatment availability of highly effective modulators. Unfortunately, not all PwCF are eligible for modulators leading to continued pulmonary exacerbations and advanced lung disease. Additionally, optimizing diagnosis and evaluation for CF in the newborn period continues to be an area of focus for research. This review article will work to cover articles published in 2021 with high clinical relevance related to the above topics, however due to the extensive body of research published, this review will not be comprehensive.

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Outcomes of Cystic Fibrosis Screening–Positive Infants With Inconclusive Diagnosis at School Age

Cited by 33 publications

References 33 publications

Refinement of newborn screening for cystic fibrosis with next generation sequencing

Refinement of newborn screening for cystic fibrosis with next generation sequencing

Increase in Sweat Chloride Concentration Is Associated with a Higher Risk of CFSPID to CF Reclassification

Cystic fibrosis year in review 2021

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