Screening Program For Cystic Fibrosis Research Articles

Children with cystic fibrosis are still receiving inconclusive diagnosis despite undergoing newborn screening.

We aimed to familiarise clinicians with the terms cystic fibrosis transmembrane conductance regulator related metabolic syndrome (CRMS) and cystic fibrosis screen positive inconclusive diagnosis (CFSPID). We also sought to highlight the monitoring and outcomes of children that match these designations. A literature review was performed by searching PubMed from its inception until 30 November 2022. All relevant articles were included in this narrative review. Despite the implementation of newborn screening programmes for cystic fibrosis (CF), the diagnosis remains uncertain in some newborn infants with elevated immunoreactive trypsinogen. In 2016, a unified definition for CRMS/CFSPID was established to categorise these children. While many of them remain healthy, a portion of these children may develop CF. As a result, it is crucial to monitor them regularly. CRMS/CFSPID is a designation and not a diagnosis. Longer longitudinal studies are needed to shed light on the most appropriate follow-up of these children. Paediatricians need to be knowledgeable about this condition in order to administer proper care, and children should be in contact with their local CF centre.

Newborn Screening Program for Cystic Fibrosis in Cuba: Three Years’ Experience

Newborn Screening Program for Cystic Fibrosis in Cuba: Three Years’ Experience

Five-year performance analysis of a cystic fibrosis newborn screening program in northeastern Brazil

ObjectiveTo analyze the performance of the cystic fibrosis (CF) newborn screening (NBS) program over its first five years in a Brazilian northeastern state. MethodA population-based study using a screening algorithm based on immunoreactive trypsinogen (IRT)/IRT. Data were retrieved from the state referral screening center registry. The program performance was evaluated using descriptive indicators such as the results of an active search, coverage, newborn's age at the time of blood sampling, the time between sample collection and its arrival at the laboratory, and the child's age at diagnosis of disease. ResultsThe public CF screening program covered 82.6% of the 1,017,576 births that occurred, with an accumulated five-year incidence of 1:20,767 live births. The median (25th-75th) age at diagnosis was 3.5 (2.3–7.3) months. The sampling before 7 days of life for the first IRT (IRT1) increased between 2013 and 2017 from 42.2 to 48.3%. Around 5% of IRT1 samples and 30% of the second samples were collected after 30 days of life. In the first and second stages of screening, 23.6% and 19.9% of the infants, respectively, were lost to follow-up. In both stages of screening, the samples were retained at the health units for a median (25th–75th) of 9.0 (7.0–13.0) days. ConclusionsThe coverage by the CF-NBS program was satisfactory as compared to other Brazilian state rates and the percentage of IRT1 samples collected within the first week of life increased progressively. However, time of samples retention at the health units, inappropriate sampling, inherent methodological problems, and loss of follow-up need to improve.

CFTR mutational screening by next-generation sequencing reveals novel variants and a high carrier rate in a Middle Eastern population.

Cystic fibrosis is the most common life-limiting autosomal recessive disease in western countries with an incidence of 1:2500 in United States and 1:1000 in some European countries. Similar incidences were noted for the Middle East with variations from 1 in 2560 to 1 in 15,876 according to the degree of consanguinity. This is a preliminary systematic study that aims to assess the incidence and carrier rate of cystic fibrosis in the Middle Eastern Lebanese population; known for a high frequency of consanguinity. One hundred thirteen DNA samples were collected from neonatal blood cards obtained from newborns to healthy unrelated families with no previous history of Cystic fibrosis. Screening for Cystic Fibrosis-causing pathogenic variants was performed using next generation sequencing, and 17 different single nucleotide variants were detected, including six pathogenic and likely pathogenic. 5.5%-7% newborns were found to be carriers of a variant strongly suggestive of pathogenicity and comparable to published literature worldwide. This pilot analysis highlights the challenging interpretation of CFTR variants in a country underrepresented by large ethnic population analyses, and stresses the importance of premarital screening programs for Cystic fibrosis.

Newborn screening for cystic fibrosis in France

Neonatal screening for cystic fibrosis has optimised the prognosis for patients allowing very early multidisciplinary care. Over the past 20 years, screening programmes have undergone major international expansion. The performances of the French neonatal cystic fibrosis screening programme, established in 2002, has met European guideline standards, with positive predictive value of 0.31 (against a minimum of 0.30) and sensitivity value of 0.95 (against a minimum of 0.95). It is also important to highlight the very high percentage of sweat tests performed (95.5%), of mutations identified (96.6%), the 9:1 ratio of cystic fibrosis cases to cases of inconclusive diagnosis achieved and the effectiveness of the strategy implemented for the detection of false negative cases. A new organisation for cystic fibrosis neonatal screening has now been established in France. It is vital that effectiveness is maintained throughout the process, from newborn maternity care to diagnosis in cystic fibrosis care centres, and that further knowledge is gained through exhaustive data collection and validation.

Defining key outcomes to evaluate performance of newborn screening programmes for cystic fibrosis

The European Cystic Fibrosis Society (ECFS) Neonatal Screening Working Group (NSWG) aims to monitor the performance of newborn bloodspot screening (NBS) for cystic fibrosis (CF) and compare protocols to optimize effectiveness, whilst reducing negative impact in agreement with published international guidelines. 1 The NSWG has supported numerous European countries and regions to establish NBS for CF. Collecting data on the performance of programmes across Europe has been a key element in evaluating and improving quality.

Current Status of Genetic Diagnosis Laboratories and Frequency of Genetic Variants Associated with Cystic Fibrosis through a Newborn-Screening Program in Turkey

Background: Cystic fibrosis (CF) is the most common worldwide, life-shortening multisystem hereditary disease, with an autosomal recessive inheritance pattern caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The national newborn screening (NBS) program for CF has been initiated in Turkey since 2015. If the immunoreactive trypsinogen (IRT) is elevated (higher than 70 μg/L in the second control) and confirmed by sweat test or clinical findings, genetic testing is performed. The aims of this study are to emphasize the effect of NBS on the status of genetic diagnosis centers with the increasing numbers of molecular testing methods, and to determine the numbers and types of CFTR mutations in Turkey. Methods: The next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) results of 1595 newborns, who were referred to Cukurova University Adana Genetic Diseases Diagnosis and Treatment Center (AGENTEM) for molecular genetic testing, were evaluated with positive CF NBS program results since 2017. Results: According to the results; 560 (35.1%) of the 1595 patients carried at least 1 (one) CF-related variant, while 1035 patients (64.9%) had no mutation. Compound heterozygosity for two mutations was the most common in patients, while two detected variants were homozygote in 14 patients. A total of 161 variants were detected in 561 patients with mutations. Fifteen novel variants that have not been previously reported were found. Moreover, p.L997F was identified as the most frequent pathogenic mutation that might affect the IRT measurements used for the NBS. The distribution of mutation frequencies in our study showed a difference from those previously reported; for example, the well-known p.F508del was the third most common (n = 42 alleles), rather than the first. The most striking finding is that 313 cases had a pathogenic variant together with the V470M variant, which might have a cumulative effect on CF perpetuation. Conclusion: This study is the first to determine the mutational spectrum of CFTR in correlation with the NBS program in the Turkish population. NBS for CF raises issues regarding screening in diverse populations, both medical and non-medical benefits, and carrier identification. Through the lens of NBS, we focused on the integrated diagnostic algorithms and their effect on the results of genetic testing.

Early Diagnosis and Intervention in Cystic Fibrosis: Imagining the Unimaginable.

Cystic fibrosis is the most common life-shortening genetic disease affecting Caucasians, clinically manifested by fat malabsorption, poor growth and nutrition, and recurrent sinopulmonary infections. Newborn screening programs for cystic fibrosis are now implemented throughout the United States and in many nations worldwide. Early diagnosis and interventions have led to improved clinical outcomes for people with cystic fibrosis. Newer cystic fibrosis transmembrane conductance regulator potentiators and correctors with mutation-specific effects have increasingly been used in children, and these agents are revolutionizing care. Indeed, it is possible that highly effective modulator therapy used early in life could profoundly affect the trajectory of cystic fibrosis lung disease, and primary prevention may be achievable.

WS06.1 Defining key outcomes to evaluate performance of newborn screening programmes for cystic fibrosis

WS06.1 Defining key outcomes to evaluate performance of newborn screening programmes for cystic fibrosis

P016 First results from national newborn screening program for cystic fibrosis in the Republic of North Macedonia

P016 First results from national newborn screening program for cystic fibrosis in the Republic of North Macedonia

Pilot study for cystic fibrosis neonatal screening: the Cuban experience.

Background In Cuba, no screening program for cystic fibrosis (CF) has been implemented yet. The ultramicro enzyme-linked immunosorbent assay (UMELISA)® TIR NEONATAL has been developed for the measurement of immunoreactive trypsin (IRT) in dried blood spots on filter paper. The analytical performance of the kit was evaluated in the national network of laboratories. Methods Newborn dried blood samples (DBS) were evaluated in 16 laboratories. An IRT/IRT/DNA protocol was followed using a cut-off value of 50 ng/mL. The mean, median and percentiles of the distribution were calculated and a two-sample t-test with unequal variance was used for statistical analysis. Influence of perinatal factors on IRT levels was analyzed. Results From January to June 2018, 6470 newborns were studied, obtaining a mean IRT value of 12.09 ng/mL (ranging 0-358 ng/mL) and a median of 8.99 ng/mL. Fifty-two samples (0.78%) were above the cut-off level and 16 samples (0.24%) were elevated in the re-screening process. One of them was confirmed positive by molecular biology (phe508del/c.3120 + 1G > A), constituting the first newborn screened and diagnosed early in Cuba. Second DBS samples were collected on average at 14 days and processed in the laboratory at 16 days of birth. Significant differences were observed (p < 0.05) when evaluating the influence of gender, birth weight (BW) and gestational age (GA) on the IRT values. Lower IRT concentrations were found in samples processed after 10 days of collection. Conclusions The performance of UMELISA® TIR NEONATAL in the laboratories has been satisfactory; hence CF newborn screening (NBS) was extended throughout the country from January 2019.

Newborn Screening for Cystic Fibrosis in Mersin Province: Yearly Assessment of the National Program.

A national newborn screening program for cystic fibrosis (CF) was started using immunoreactive trypsinogen (IRT) test on January 1, 2015, in Turkey. We aimed to analyze the characteristics of newborn screen-positive (NBSP) infants in Mersin province. The data on NBSP infants were retrospectively analyzed between 2015 and 2017 from records of Mersin Women & Children's Hospital and Mersin City Training and Research Hospital. A total of 82,273 newborns were screened for CF by IRT test between January 2015 and December 2017 in Mersin. Among those, 512 infants were defined as NBSP after two repeated IRT tests (IRT/IRT) (138 infants in 2015, 217 in 2016, and 157 in 2017). Sweat test was normal in the majority of infants (115 infants [83.3%] in 2015, 189 [87.1%] in 2016, and 129 [82.2%] in 2017). Overall, between 2015 and 2017, after two repeated sweat tests, 4 infants had sweat test results in the intermediate range and 9 infants had positive sweat tests. The incidence of CF for a 3-year period was approximately 1/9300 in our region. The positive predictive value of IRT test for defining CF was 1.8%, with a sensitivity of 90.0% and specificity of 99.4%. IRT/IRT test as a newborn screening strategy provides the opportunity for earlier diagnosis and treatment of CF patients. More data are needed to understand the frequency of CF on a national level.

Cystic fibrosis newborn screening in Denmark: Experience from the first 2 years.

In Denmark, newborn screening (NBS) for cystic fibrosis (CF) was introduced on 1 May 2016. The implementation and results from the first 2 years of the national newborn CF screening program are presented. The screening included immunoreactive trypsinogen (IRT), followed by evaluation for the F508del mutation when a value at or above the 50 ng/mL cutoff was present. In cases with a single F508del mutation or a very high IRT value above 145 ng/mL, next-generation sequencing of the CF transmembrane conductance regulator gene (CFTR) was performed. Of 126 522 newborn infants 126 338 were tested (99.85%), and 4730 samples (3.7%) were assessed for CFTR mutations. Twenty-six infants were screen-positive and referred for diagnostic follow-up of whom 22 were confirmed to have a CF diagnosis, four had one known and one CFTR allele with unknown pathogenicity, classified as cystic fibrosis screening positive inconclusive diagnosis (CFSPID), PPV 84.6%. One of the four children classified as CFSPID was later found to carry the two identified CFTR variants in cis and was reclassified as a carrier of CF. We found two false negatives; one exhibited an IRT level above the 50 ng/mL cutoff but was below the 145 ng/mL very high cutoff and with no F508del mutation present. The second false-negative fell below the 50 ng/mL IRT cutoff but was diagnosed shortly after birth on the basis of meconium ileus. Screening sensitivity, 91.7%. Two hundred thirty-two children were identified as carriers of CF, which is twofold above the estimated annual number of carriers. All but one carrier were heterozygous for the F508del CFTR mutation. Sixteen percent of the sequenced samples revealed rare CFTR variants, which were classified as nonpathogenic in relation to CF. During the first 2 years of NBS CF screening in Denmark, we identified close to the expected number of infants with CF using an algorithm based on IRT, presence of F508del mutation and comprehensive genetic analysis. CFSPID accounted for only a small minority, despite comprehensive CFTR sequencing, whereas more carriers than initially expected were identified.

How to Manage Antibiotic Allergy in Cystic Fibrosis? Epidemiologic, Diagnostic, and Therapeutic Aspects

Cystic fibrosis (CF) is a complex genetic disease with high mortality, of which 85% is a result of lung disease characterized by serious endobronchial infections. Antibiotic therapy is one of the main treatments of CF, both during acute exacerbations and as chronic maintenance medications, contributing to a prolonged survival. Since neonatal CF screening programs have been implemented universally and the longevity of patients with CF steadily increases, antibiotic hypersensitivity reactions (HSRs) are becoming more important. HSR to antibiotics in CF has been reported since the 1980s and was estimated to occur up to three times more frequently in these patients, probably owing to high rates of antibiotic exposure and boosting stimuli such as infections and inflammation. However, recent studies including large groups of CF patients with a suspicion of antibiotic allergy have used diagnostic algorithms including skin tests and drug provocation tests and showed that true incidence was much lower. The mechanism of the reactions and the clinical presentations are not different in CF than in the general population. Both the immediate and nonimmediate type HSRs are seen, and among the latter, drug fever and drug-induced hemolytic anemia are distinctive presentations. Beta-lactam (BL) agents are the most common cause, with higher rates for ureidopenicillins (piperacillin, mezlocillin, and piperacillin/tazobactam) and cephalosporins (especially ceftazidime), intermediate rates for carbapenems, and lowest rates for aztreonam, and also HSRs to aminoglycosides, macrolides, and quinolones are encountered. Since the available choices for antibiotic therapy are limited due to relevant organisms, management becomes a challenge. It is essential to evaluate the patients according to the mechanism of the HSR and determine the risk of repeat administration of the culprit drug and also safety of alternative drugs with prior skin and provocation tests. The chemical structure and side chains must be taken into account when selecting a safe alternative drug. Contrary to what was previously thought, recent data on cross-reactions between BL antibiotics showed that some BLs can be an option of treatment for patients allergic to other BLs. Desensitization is a useful procedure in immediate and some delayed reactions, if a suitable alternative antibiotic is not available.

Brazilian guidelines for the diagnosis and treatment of cystic fibrosis.

ABSTRACTCystic fibrosis (CF) is an autosomal recessive genetic disorder characterized by dysfunction of the CFTR gene. It is a multisystem disease that most often affects White individuals. In recent decades, various advances in the diagnosis and treatment of CF have drastically changed the scenario, resulting in a significant increase in survival and quality of life. In Brazil, the current neonatal screening program for CF has broad coverage, and most of the Brazilian states have referral centers for the follow-up of individuals with the disease. Previously, CF was limited to the pediatric age group. However, an increase in the number of adult CF patients has been observed, because of the greater number of individuals being diagnosed with atypical forms (with milder phenotypic expression) and because of the increase in life expectancy provided by the new treatments. However, there is still great heterogeneity among the different regions of Brazil in terms of the access of CF patients to diagnostic and therapeutic methods. The objective of these guidelines was to aggregate the main scientific evidence to guide the management of these patients. A group of 18 CF specialists devised 82 relevant clinical questions, divided into five categories: characteristics of a referral center; diagnosis; treatment of respiratory disease; gastrointestinal and nutritional treatment; and other aspects. Various professionals working in the area of CF in Brazil were invited to answer the questions devised by the coordinators. We used the PubMed database to search the available literature based on keywords, in order to find the best answers to these questions.

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.

EPS01.4 Improvement of the validity of the Dutch combined IRT/PAP/InnoLiPA/EGA newborn screening program for cystic fibrosis by re-evaluating mutation classification and optimizing cut-off values

ePS01.4 Improvement of the validity of the Dutch combined IRT/PAP/InnoLiPA/EGA newborn screening program for cystic fibrosis by re-evaluating mutation classification and optimizing cut-off values

17 New cystic fibrosis screening programme and first findings in middle Anatolian city

17 New cystic fibrosis screening programme and first findings in middle Anatolian city

Implementation of newborn screening for cystic fibrosis in Norway. Results from the first three years

BackgroundNorway introduced newborn screening for cystic fibrosis (CF) March 1, 2012. We present results from the first three years of the national newborn CF screening program. MethodsPositive primary screening of immunoreactive trypsinogen (IRT) was followed by DNA testing of the Cystic fibrosis transmembrane conductance regulator (CFTR) gene. Infants with two CFTR mutations were reported for diagnostic follow-up. ResultsOf 181,859 infants tested, 1454 samples (0.80%) were assessed for CFTR mutations. Forty children (1:4546) had two CFTR mutations, of which only 21 (1:8660) were confirmed to have a CF diagnosis. The CFTR mutations differed from previously clinically diagnosed CF patients, and p.R117H outnumbered p.F508del as the most frequent mutation. One child with a negative IRT screening test was later clinically diagnosed with CF. ConclusionsThe CF screening program identified fewer children with a conclusive CF diagnosis than expected. Our data suggest a revision of the IRT/DNA protocol.

Attitudes of cystic fibrosis patients and parents toward carrier screening and related reproductive issues.

Cystic fibrosis (CF) is a life-limiting autosomal recessive disorder affecting ~1 in 2500-4000 Caucasians. As most CF patients have no family history of the disorder, carrier screening for CF has the potential to prospectively identify couples at risk of conceiving an affected child. At-risk couples may consequently choose to act on the provided information and take steps to avoid the birth of a child with CF. Although carrier screening is widely believed to enhance reproductive autonomy of prospective parents, the practice also raises important ethical questions. A written questionnaire was administered to adult patients and parents of children with CF with the aim to explore participants' attitudes toward CF carrier screening and related reproductive issues. The study population was recruited from a CF patient registry in Belgium and comprised 111 participants (64 parents, 47 patients aged 16 or older). We found that more than 80% of all participants were in favor of preconception carrier screening for CF. However, some were concerned over potential negative consequences of population-wide CF carrier screening. Regarding future reproductive intentions, 43% of the participants indicated a desire to have children. Among these, preimplantation genetic diagnosis was found to be the most preferred reproductive option, closely followed by spontaneous pregnancy and prenatal diagnosis. Although the findings of our study suggest that patients and parents of children with CF support a population-based carrier screening program for CF, they also highlight some issues deserving particular attention when implementing such a program.