Neonatal screening for cystic fibrosis: A comparison of two strategies for case detection in 1.2 million babies

doi:10.1016/S0022-3476(95)70040-4

The Journal of Pediatrics

Volume 127, Issue 6, December 1995, Pages 965-970

https://doi.org/10.1016/S0022-3476(95)70040-4 Get rights and content

Abstract

Objectives: To review the overall performance of a neonatal screening program for cystic fibrosis (CF) from 1981 to 1994, and to compare two strategies of case detection. Program design: Initially, immunoreactive trypsin (IRT) was measured in dried blood spots, and because of the low sensitivity of this test at days 3 to 5, a second sample was needed from babies with positive test results. Since 1993 a positive IRT assay result has been followed by direct gene analysis for the common CF mutation, ΔF508, with the use of the same sample. Cases with false-negative results were actively sought throughout the period. Results: With IRT alone, 1,015,000 babies were tested. Of 389 babies with CF, 30had a clinical diagnosis of CF made after a negative screening test result or an administrative error. Early diagnosis was achieved in 92%. With the IRT/DNA protocol, 59 of 62 infants had a positive screening test result (44 were homozygous for ΔF508) among 189,000 babies tested. Three babies with CF had no copy of this mutation, but two were identified early because of meconium ileus. The false-positive rate was much greater for IRT alone than for the IRT/DNA test (0.69% vs 0.054%). All false-positive cases in the IRT/DNA protocol were, of necessity, CF carriers. Conclusion: The percentage of babies with CF who had an early diagnosis was similar with the two protocols, but we concluded that the advantages of the IRT/DNA test for screening, particularly in the avoidance of the need for second IRT samples, outweighed the drawback of unwanted carrier detection. (J Pediatr1995;127:965-70)

Section snippets

Population tested

All babies born in New South Wales and the Australian Capital Territory are offered a screening test for several genetic metabolic disorders. The compliance has been more than 99%. Since mid-July 1981 in New South Wales, and January 1986 in the Australian Capital Territory, a test for CF was performed as part of this screening program.

Samples

Blood samples were collected by heel prick onto No. 903 paper (Schleicher & Schuell Inc., Keene, N.H.) when babies were 48 hours of age or more, and usually on

First protocol (IRT alone)

We tested 1,015,000 babies using the first protocol, of whom 7362 (0.7%) had a positive result. At least 42 of these babies are known to have died in the neonatal period, including at least 12 with trisomy 13 or 18. Among the remaining 7320 babies, second samples were received from all except 149, a compliance rate of 98%. In an unknown number of the 149, the baby's local physician had arranged a sweat test in lieu of sending the second sample, and we were notified of 30 such infants, two of

DISCUSSION

The IRT testing alone has provided an early diagnosis for 92% of babies with CF, but among patients who were not already at high risk (siblings or babies with meconium ileus), the test failed to identify 11% of affected babies. This group of 11% did not primarily comprise patients with mild CF; the test readily identifies babies with pancreatic sufficiency.¹⁹ The IRT protocol also had the drawback that the positive predictive value of the first test was only 5.1%, and a large number of babies

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Newborn screening (NBS) provides an opportunity for early identification, and thereby early treatment, of newborns with disorders in which the clinical complications develop postnatally and may go unrecognized prior to irreversible clinical damage. Since its inception nearly six decades ago, with screening for a single disorder, NBS has expanded substantially to more than 60 disorders in the current screening panels. NBS is a “screen,” and individuals should not be labeled as having a disorder before diagnostic testing confirms the condition. However, once a disorder has been confirmed, treatment should be initiated without delay to prevent its clinical presentation and complications. Note that false positives are inevitable and that false negatives are possible. The clinical spectrum of disorders identified through NBS is often wider than expected, and the disorder detected is not always the one that was sought. Numerous methods are used in NBS, ranging from simple to complex, such as isoelectric focusing and enzymatic assays to tandem mass spectrometry and high-throughput genomic sequencing. Many factors will continue to transform NBS, including rapidly advancing technology, and new and increasingly available therapeutic approaches to previously untreatable disorders. This chapter provides a brief history and covers the concepts, criteria, processes, and limitations of newborn screening. The methodologies employed and screened specific issues related to disorders in the current panels are also included.
Sexual dimorphism in the microbiology of the CF ‘Gender Gap’: Estrogen modulation of Pseudomonas aeruginosa virulence
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There is increasing evidence for sexual dimorphism of estrogen (E2) actions in the exacerbation of lung function, infection and inflammation in females with cystic fibrosis - the so-called “CF gender gap”. The effects of estrogen on virulence factors that enhance P. aeruginosa persistence in CF lung epithelium were investigated by phenotypic and chemical assays in various PsA clinical isolates and laboratory strains in isolation or in co-culture with normal (Nuli-1) and CF dPhe508-CFTR (CuFi-1) human bronchial epithelial cell lines. Estrogen (E2, 10 nM) significantly increased secretion of the virulence factor pyocyanin by 80% in PsA early infection isolates from female CF patients and by 280% in late infection PsA isolates. Estrogen also increased the swarming motility by up to 50% in all PsA isolates and strains tested in 0.5% agar. A significant increase of 110% in the twitching motility of all PsA isolates and strains tested was also observed with estrogen treatment. Treatment with E2 increased biofilm formation of P. aeruginosa PsAO1 which became more adherent to, and invasive into, normal and CF bronchial epithelial cells. The selective estrogen receptor modulators (SERMs), Tamoxifen and ICI 182780 inhibited P. aeruginosa motility. The potency of various steroid hormones to stimulate motility of P. aeruginosa was in the order; estradiol ≫ estrone > E3 estriol ≥ testosterone ≥ progesterone ≫ aldosterone, cortisol. Estrogen was also shown to reduce ciliary beat intensity in CF bronchial epithelium which would further exacerbate PsA trapping and virulence in the CF airways. In conclusion, we have demonstrated for the first time that estrogen exacerbates P. aeruginosa virulence factors and enhances bacterial interactions with CF bronchial epithelium which can be inhibited by tamoxifen. Our work suggests that SERMs could be used as an adjuvant treatment to reduce estrogen-induced P. aeruginosa infections and associated lung exacerbations in females with CF.
Cystic fibrosis screen positive inconclusive diagnosis (CFSPID): Experience in Tuscany, Italy
2019, Journal of Cystic Fibrosis
The implementation of cystic fibrosis (CF) newborn screening (NBS) has led to identification of infants with a positive NBS test but inconclusive diagnosis classified as “CF screen positive, inconclusive diagnosis” (CFSPID). We retrospectively evaluated the prevalence and clinical outcome of CFSPID infants diagnosed by 2 NBS algorithms in the period from 2011 to 2016 in the Tuscany region of Italy.
In 2011–2016, we assessed the diagnostic impact of DNA analysis on the NBS 4-tier algorithm [immunoreactive trypsin (IRT) – meconium lactase – IRT2 – sweat chloride (SC)]. All CFSPID patients repeated SC testing every 6 months, and CFTR gene analysis was performed (detection rate 98%). We reclassified children as: CF diagnosis in presence of at least 2 pathological SC results; healthy carrier or healthy in presence of at least 2 normal SC results for age and either 1 or 0 CF-causing mutations, respectively.
We identified 32 CF and 50 CFSPID cases: 20/50 (40%) were diagnosed only by the IRT-DNA-SC algorithm and 16/50 (32%) only by IRT-meconium lactase-IRT2-SC. Both protocols identified the remaining 14 cases (28%). Thirty-seven of 50 (74%) CFSPID patients had a conclusive diagnosis on December 31, 2017:5 (10%) CF, 17 (34%) healthy and 15 (30%) healthy carriers; 13/50 (26%) cases were asymptomatic with persistent intermediate SC and followed as CFSPID (CF:CFSPID ratio 2.85:1).
In 6 years, the CF:CFSPID ratio modified from 0.64:1 to 2.85:1, and 10% of CFSPID cases progressed to CF. Genetic analysis improved positive predictive value and identified a higher number of CFSPID infants progressing to CF.
Cystic fibrosis
2019, Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics: Cardiovascular, Respiratory, and Gastrointestinal Disorders
Cystic fibrosis (CF) is one of the most common autosomal recessive disorders associated with decreased longevity in the Caucasian population. The disease is classically described as a triad; chronic obstructive pulmonary disease, exocrine pancreatic insufficiency, and elevation of chloride concentration in sweat. The underlying pathophysiology involves abnormal ion transport due to dysfunction of the CF transmembrane conductance regulator (CFTR). Altered salt and water movement across epithelia interferes with the hydration and ionic composition of mucus secretions. Abnormal mucus impairs clearance and defense systems, leading to inflammation and destruction of the lungs, the pancreas, and the developing vas deferens in males. The development of bioavailable small molecules that augment CFTR function is revolutionizing the treatment of CF.
Results of the Andalusian Cystic Fibrosis Neonatal Screening Program, 5 Years After Implementation
2018, Archivos de Bronconeumologia
Andalucía dispone de screening neonatal de fibrosis quística (SNFQ) desde mayo 2011, basado en doble determinación de tripsinógeno inmunorreactivo ([TIR] [TIR1/TIR2]). Si el screening es positivo realizamos un test del sudor y si es positivo o dudoso solicitamos genética.
Analizar el SNFQ, basado en los resultados de los primeros 4,5 años.
Estudio descriptivo prospectivo de los neonatos sometidos a SNFQ. Se recogen los niveles de TIR, cloruro en sudor, mutaciones. Mediante SPSS12.0 se realizó análisis estadístico.
Desde mayo 2011 a diciembre 2016, 474.953 neonatos fueron sometidos a SNFQ. Mil ochenta y siete (0,23%) presentaron TIR2 elevado. Desde la implantación del SNFQ se diagnosticaron 73 casos con fibrosis quística; 60 de ellos fueron diagnosticados mediante un SNFQ positivo, mientras que 13 no. Concretamente un paciente comenzó con clínica clásica de fibrosis quística y se comprobó que no se había realizado el SNFQ por decisión paterna; los 12 restantes tuvieron un SNFQ negativo (falsos negativos). De estos, un paciente fue diagnosticado presintomáticamente al tener su hermano gemelo con SNFQ positivo; otro con cloruro en el límite alto de la normalidad se diagnosticó presintomáticamente mediante genética; 10 pacientes comenzaron clínicamente. Excluyendo los pacientes con íleo meconial, la sensibilidad y especificidad del programa de SNFQ asciende al 85,71 y 99,78% respectivamente. La incidencia de la enfermedad en Andalucía es de 1/6.506 recién nacidos vivos.
Los presentes resultados nos permiten reflexionar sobre posibles áreas de mejoras adicionales del algoritmo del SNFQ, que debe pasar por la introducción de estudios genéticos para así aumentar la sensibilidad y disminuir los falsos positivos.
Cystic fibrosis neonatal screening (CFNS), based on double determination of immunoreactive trypsinogen ([IRT] [IRT1/IRT2]), has been available in Andalusia since May 2011. If screening is positive, a sweat test is performed, and if that is positive or inconclusive, genetic testing is requested.
To analyze CFNS, based on results from the first 4.5 years of the program.
Prospective descriptive study of neonates undergoing CFNS. IRT levels, sweat chloride, and mutations were recorded. Statistical analysis was performed using SPSS 12.0.
Between May 2011 and December 2016, 474,953 neonates underwent CFNS. Of these, 1,087 (0.23%) had elevated IRT2. Since CFNS was introduced, 73 cases of cystic fibrosis were diagnosed; 60 were diagnosed by positive CFNS, and 13 were diagnosed by other means. In one case, the patient developed a typical clinical picture of cystic fibrosis, but had not undergone CFNS at the decision of the parents; the remaining 12 had a negative CFNS (false negatives). Of these, one patient was diagnosed before symptoms developed, as his twin brother had a positive CFNS result; another had chloride at the upper limit of normal, and was subsequently diagnosed with genetic testing before symptoms appeared; and 10 patients developed clinical signs and symptoms. Excluding patients with meconium ileus, sensitivity and specificity of the CFNS program were 85.71% and 99.78%, respectively. The incidence of the disease in Andalusia is 1/6,506 live births.
These results are a basis for reflection on possible areas for improvement of the CFNS algorithm, and thought may be given to the introduction of genetic studies to increase sensitivity and reduce false positives.
Newborn Screening
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^☆: From the New South Wales Newborn Screening Program, Royal Alexandra Hospital for Children, Sydney, Australia

^☆☆: Reprint requests: Bridget Wilcken, FRACP, Royal Alexandra Hospital for Children, Post Office Box 3515, Parramatta (Sydney) 2124, Australia.

^★: 0022-3476/95/$5.00 + 0 9/23/67543

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Neonatal screening for cystic fibrosis: A comparison of two strategies for case detection in 1.2 million babies☆,☆☆,★

Abstract

Section snippets

Population tested

Samples

First protocol (IRT alone)

DISCUSSION

J PEDIATR

Lancet

Lancet

Lancet

Screening

Lancet

Biochem Med Metab Biol

Dried blood spot screening for cystic fibrosis in the newborn

Lancet

Screening for cystic fibrosis by dried blood spot trypsin assay

Arch Dis Child

Efficacy of statewide screening for cystic fibrosis by assay of trypsinogen concentrations

N Engl J Med

Parents' knowledge of neonatal screening and response to false-positive cystic fibrosis testing

Dev Behav Pediatr

Neonatal screening strategy for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis

BMJ

Neonatal screening for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis : four years' experience

BMJ