Screening for cystic fibrosis. A comparative study

A neonatal screening program for CF by determination of albumin in meconium was performed in the north eastern part of the Netherlands from 1973 to 1979. In this period 94,043 newborns were screened and 116,953 were not. A follow-up study of CF patients in the above cohorts was started in 1980. The purposes of this study were to evaluate the effects of early diagnosis and treatment in CF patients by comparing the outcome in the two groups of patients. Although the results indicate that very early diagnosis and treatment have a beneficial effect on outcome, more studies are needed before a definite answer can be given as to whether or not mass neonatal screening should be started.     

Screening for Cystic Fibrosis

ABSTRACT. A neonatal screening program for CF by determination of albumin in meconium was performed in the north eastern part of the Netherlands from 1973 to 1979. In this period 94043 newborns were screened and 116953 were not. A follow-up study of CF patients in the above cohorts was started in 1980. The purposes of this study were to evaluate the effects of early diagnosis and treatment in CF patients by comparing the outcome in the two groups of patients. Although the results indicate that very early diagnosis and treatment have a beneficial effect on outcome, more studies are needed before a definite answer can be given as to whether or not mass neonatal screening should be started.     

DIAGNOSIS AND MAIN CLINICAL FEATURES OF CYSTIC FIBROSIS WITH SPECIAL ATTENTION TO SCREENING PROCEDURES

Kollberg, H. (Department of Paediatrics, University of Umeå, Umeå, Sweden). Diagnosis and main clinical features of cystic fibrosis with special attention to screening procedures. Acta Paediatr Scand 1982; suppl 301:15-25. – The diagnosis of cystic fibrosis (CF) must be based on a combination of clinical observations of all symptoms and the results of laboratory tests. The numerous symptoms from the respiratory and gastrointestinal tracts and from the sweat glands are briefly described and the specific diagnostic tests referring to these systems are enumerated. CF is a common disease which constitutes a substantial problem both for the individuals concerned and for the community. Screening most probably would result in an improvement for the early diagnosed patients with respect both to survival and to physical function. The society has the means to provide resources both for confirming the diagnosis and for providing complete long-term therapy for CF patients, but the diagnostic and therapeutic possibilities need to be organized more firmly. Alternative ways of diagnosis other than screenning are unsatisfactory and lead to a diagnostic delay which most probably is detrimental for the patient. Promising screening tests are on the way; the test for trypsin in serum, in particular, seems to be specific, non-injurious to the patient and applicable to all newborns in countries with Caucasian populations, but it remains to be seen whether it is sufficiently sensitive and inexpensive. It is concluded that CF is a top ranked candidate for general screening in the neonatal period and further intensive studies in this field must get every support. The multicentre study for screening, proposed and supported by ICF(M)A is heartily welcomed.     

Failure to thrive: the earliest feature of cystic fibrosis in infants diagnosed by neonatal screening

The benefits of early treatment of nutritional and respiratory problems in the CF infant and of genetic counselling for the parents are widely recognized. However, clinical diagnosis of CF is often delayed despite early onset of symptoms and the usefulness of neonatal population screening as a preventive measure is still under debate. This study analyses the clinical history of CF patients diagnosed exclusively on the basis of positive neonatal screening tests with the aim of identifying the earliest markers of the disease. We studied 103 CF infants bom in north-east Italy, diagnosed following neonatal screening: assay of immunoreactive trypsin (IRT) from a heel-prick blood sample followed by a measurement of meconium lactase in cases with raised IRT. Diagnosis was confirmed by sweat test at an average age of 39 days. Eighty-one patients (79%) had symptoms strongly suggestive of CF at diagnosis, and signs and/or symptoms of pancreatic insufficiency were present in 16 of the remaining 22 cases. The most frequent symptom was growth failure (69% of infants) and of these. 44% weighed the same as at birth or less. Pancreatic insufficiency was confirmed by the low level of faecal chymotrypsin found in 85% of cases. IRT was elevated in all cases. CF had not been suspected in any symptomatic infant, although most of the infants had been monitored by a paediatrician. In conclusion, most infants with CF diagnosed by neonatal screening are already symptomatic in the first six weeks of life and the most frequent symptom is failure to thrive; pancreatic insufficiency was already present in most cases. In areas without CF neonatal screening programs, the disease should be excluded by differential diagnosis in all cases with growth failure notwithstanding adequate caloric intake in the first months of life. The high sensitivity, low cost and simple execution of IRT and fecal chymotrypsin tests make them an ideal first step in suspect cases before proceeding to the sweat test, often performed late because of limited availability.     

Neugeborenenscreening auf Zystische Fibrose (CF)

Neonatal screening for CF now seems to fit the generally accepted criteria for screening. Cystic fibrosis is a common, clinically and biochemically well-defined disorder with significant morbidity and mortality. Clinical diagnosis may be delayed until lung damage has occurred and endobronchial infection may start within the first weeks of life. Active treatment improves clinical status and survival of CF-patients. Safe, simple and effective screening tests are available. Nevertheless, routine screening of newborns for cystic fibrosis has not had universal approval because of uncertainty about its benefits and potential harm by unwanted carrier detection. Evidence for longterm nutritional as well as pulmonary benefits is accumulating from recent carefully conducted observational studies and from the prospective, controlled trial in Wisconsin. In addition, many CF professionals and parents universally support neonatal screening. Several aspects must be considered before the introduction of neonatal screening for cystic fibrosis to optimise reliable and prompt performance of the screening programme: prompt follow up of individuals with abnormal screening test; accurate diagnosis of individuals with a reliable, standardised confirmatory test; education, genetic counseling and psychosocial support for families with affected children; appropriate medical management for patients. Carefully organised screening programmes with systematic outcome evaluations will provide new opportunities to gather data about the effects of different early intervention modalities on preventing morbidity, disability and mortality associated with CF.     

Protocolo de seguimiento de pacientes con fibrosis quística diagnosticados por cribado neonatal

Newborn screening (NBS) for cystic fibrosis (CF) is well-established in many countries and provides the opportunity for an early diagnosis and treatment before the development of irreversible structural lung damage.In 1999, Catalonia, Castilla-León, and the Balearic Islands started the NBS programme for CF. In the last 10 years its implementation rapidly spread and all the autonomies offer the NBS programme for CF since 2015. There are many different strategies across Spain. It is believed that it is very opportune to have an updated and consensual guide for the diagnosis, follow-up, and treatment of patients diagnosed by neonatal screening.     

Reproductive decisions after neonatal screening identifies cystic fibrosis

AIMS: To document the reproductive choices made by women in New South Wales, Australia, after neonatal screening has identified cystic fibrosis (CF). METHODS: A sample of women attending cystic fibrosis clinics in New South Wales who had a child (or children) diagnosed by neonatal screening between 1981 and 1996 were interviewed. RESULTS: Two thirds of the women chose to avoid having another child with CF. The uptake of prenatal diagnosis was 66% in women who had a subsequent pregnancy; of these 69% terminated or would have terminated an affected fetus. Fifty nine per cent of the women who decided against a further pregnancy made this decision in order to avoid having another child with CF. CONCLUSIONS: These data show that having a child with CF influenced subsequent reproductive choices. In addition to the medical advantages of an early diagnosis offered by neonatal screening, this also allows informed future reproductive decisions.     

State-of-the-art for DNA technology in newborn screening

Just as metabolites, hormones and proteins are measured in newborn screening tests, DNA has become an analyte that is important in the screens for certain disorders. DNA confirmatory testing on the original dried blood specimen reduces the age at diagnostic confirmation and antibiotic prophylaxis initiation for neonates with sickle cell disease. Molecular genetic analysis of the initial specimens from newborns with elevated immunoreactive trypsinogen (IRT) for cystic fibrosis (CF) screening permits reduction of the IRT threshold value, improving specificity without compromising sensitivity. Because of this cost reduction, CF neonatal screening programs routinely incorporate DNA confirmatory testing into their initial CF screening algorithm. DNA analysis is also a valuable adjunct in screening programs for congenital adrenal hyperplasia (CAH), improving sensitivity and specificity. Incorporation of DNA into newborn screening programs will continue to be stimulated by development of robust, high throughput technologies for evaluation of this analyte. New paradigms for neonatal screening are evolving, including hearing screening in the newborn nursery. DNA testing, such as for mutations in the connexin 26 gene, may have a role in the evaluation of those screened positive. Newborn screening dried blood specimens are DNA databases. Therefore, there are significant ethical, legal and social issues that must be considered in the storage and utilization of neonatal screening specimens.     

State-of-the-art for DNA technology in newborn screening

Just as metabolites, hormones and proteins are measured in newborn screening tests, DNA has become an analyte that is important in the screens for certain disorders. DNA confirmatory testing on the original dried blood specimen reduces the age at diagnostic confirmation and antibiotic prophylaxis initiation for neonates with sickle cell disease. Molecular genetic analysis of the initial specimens from newborns with elevated immunoreactive trypsinogen (IRT) for cystic fibrosis (CF) screening permits reduction of the IRT threshold value, improving specificity without compromising sensitivity. Because of this cost reduction, CF neonatal screening programs routinely incorporate DNA confirmatory testing into their initial CF screening algorithm. DNA analysis is also a valuable adjunct in screening programs for congenital adrenal hyperplasia (CAH), improving sensitivity and specificity. Incorporation of DNA into newborn screening programs will continue to be stimulated by development of robust, high throughput technologies for evaluation of this analyte. New paradigms for neonatal screening are evolving, including hearing screening in the newborn nursery. DNA testing, such as for mutations in the connexin 26 gene, may have a role in the evaluation of those screened positive. Newborn screening dried blood specimens are DNA databases. Therefore, there are significant ethical, legal and social issues that must be considered in the storage and utilization of neonatal screening specimens.     

Evaluation of growth and changes in body composition following neonatal diagnosis of cystic fibrosis

Early deficits in nutritional status that might require specific treatment and early response to nutritional therapy were studied longitudinally in 25 infants with cystic fibrosis (CF) diagnosed by neonatal screening, using anthropometric and research body composition methodology, and evaluation of pancreatic function. At the time of confirmed diagnosis (mean 5.4 weeks), body mass, length, total body fat (TBF), and total body potassium (TBK) were all significantly reduced. Following diagnosis and commencement of therapy there was a normalization of weight, length, and TBK by 6-12 months of age, indicating catch-up growth. But in some individuals the response was incomplete, and as a group, mean total body fat remained significantly lower than normal at 1 year of age. Seven of 25 (28%) were pancreatic sufficient at diagnosis, and all but one had evidence of declining pancreatic function requiring the institution of pancreatic enzyme therapy during the next 1-9 months. The median age of commencement of enzyme therapy was 10 weeks (range 5 weeks to 11 months). These longitudinal assessments emphasize the dynamic changes occurring in absorptive function, body composition, and nutritional status following neonatal diagnosis of cystic fibrosis and may reflect previously described abnormalities of energy metabolism in this age group. Abnormal body composition is evident in most CF infants following diagnosis by neonatal screening but pancreatic damage may still be evolving. We suggest that early active nutritional therapy and surveillance for changes in pancreatic function are warranted in CF infants diagnosed by neonatal screening.     

Good care for people with cystic fibrosis

The improvement in the health and survival of people who have cystic fibrosis (CF) has been due to better treatment developed at major CF centres. The regimens for prevention, early treatment and later stabilization of chronic respiratory infection and for the maintenance of normal nutrition and growth are now largely established. Treatment is life-long, complex and expensive. It should be started early after a diagnosis made following neonatal screening, and before chronic respiratory infection and malnutrition are established. Regular monitoring and input from the expert staff of a CF centre is essential, either on a 'full' or 'shared care' basis; adults with CF should attend a major Adult CF unit. The details of the staff and facilities necessary to achieve good care for CF are discussed, including the details of clinic procedures and annual assessments.     

Genetic and clinical features of false-negative infants in a neonatal screening programme for cystic fibrosis

A study was performed on the delayed diagnosis of cystic fibrosis (CF) in infants who had false-negative results in a neonatal screening programme. The genetic and clinical features of false-negative infants in this screening programme were assessed together with the efficiency of the screening procedure in the Lombardia region. In total, 774 687 newborns were screened using a two-step immunoreactive trypsinogen (IRT) (in the years 1990-1992), IRT/IRT + delF508 (1993-1998) or IRT/IRT + polymerase chain reaction (PCR) and oligonucleotide ligation assay (OLA) protocol (1998-1999). Out of 196 CF children born in the 10 y period 15 were false negative on screening (7.6%) and molecular analysis showed a high variability in the genotypes. The cystic fibrosis transmembrane regulator (CFTR) gene mutations identified were delF508, D1152H, R1066C, R334W, G542X, N1303K, F1052V, A120T, 3849 + 10kbC →T, 2789 + 5G →A, 5T-12TG and the novel mutation D110E. In three patients no mutation was identified after denaturing gradient gel electrophoresis of the majority of CFTR gene exons.

Conclusion: The clinical phenotypes of CF children diagnosed by their symptoms at different ages were very mild. None of them presented with a severe lung disease. The majority of them did not seem to have been damaged by the delayed diagnosis. The combination of IRT assay plus genotype analysis (1998-1999) appears to be a more reliable method of detecting CF than IRT measurement alone or combined with only the delF508 mutation.     

Le dépistage néonatal de la mucoviscidose en France et dans le monde. Organisation,bénéfices,difficultés. État des lieux en 2007

Newborn screening (NBS) for cystic fibrosis (CF) began more than 40 years ago. After using a screening test with meconium albumin, a twin test (rate of blood immunoreactive trypsin on blotting paper and search for main mutations of CFTR gene) is now performed routinely with good sensibility and specificity. This screening has been debatable for a long time, but it benefits, at least in the medium-term, particularly on nutritional status, are now well proved. The interest of this screening is reminded through the French and foreign experiences. Its results depend on the quality of children follow-up by specialized centres. From then on, this neonatal screening makes sense only when backed up with this kind of follow-up. That is why the spread of CF neonatal screening for the whole France in 2002 has been accompanied by recommendations for screened children to be follow-up in specialized centres: “centres de resources et de compétences de la mucoviscidose” (CRCM: resources and competences centres for CF). Two million seven hundred seventeen thousand nine hundred (and) ninety-two screened neonates (2002-Dec 31, 2005): 621 CF patients were diagnosed; the incidence of CF diagnosed through NBS was lower than expected 1/4376 with important regional variations. Fourteen percentage of the NBS CF patients resulted from dilemma cases either with a borderline sweat test plus 1 or 0 mutation or a borderline/normal sweat test with 2 mutations. A longer follow-up is needed to establish the clinical long-term outcome of these non-classical CF. Evaluating benefits and risks of this newborn screening for CF, the CDC believe that is now justified.     

Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report

Newborn screening (NBS) for cystic fibrosis (CF) is increasingly being implemented and is soon likely to be in use throughout the United States, because early detection permits access to specialized medical care and improves outcomes. The diagnosis of CF is not always straightforward, however. The sweat chloride test remains the gold standard for CF diagnosis but does not always give a clear answer. Genotype analysis also does not always provide clarity; more than 1500 mutations have been identified in the CF transmembrane conductance regulator (CFTR) gene, not all of which result in CF. Harmful mutations in the gene can present as a spectrum of pathology ranging from sinusitis in adulthood to severe lung, pancreatic, or liver disease in infancy. Thus, CF identified postnatally must remain a clinical diagnosis. To provide guidance for the diagnosis of both infants with positive NBS results and older patients presenting with an indistinct clinical picture, the Cystic Fibrosis Foundation convened a meeting of experts in the field of CF diagnosis. Their recommendations, presented herein, involve a combination of clinical presentation, laboratory testing, and genetics to confirm a diagnosis of CF.     

Why screen for cystic fibrosis? A clinician's view

Cystic fibrosis (CF) is relatively common, serious, and causes progressive lung damage. Clinical diagnosis may be delayed until lung damage has occurred, and infection may start as early as six weeks of life. A well organised screening programme should identify the great majority of affected infants within the first three weeks after birth, which leaves a small time window during which effective preventive treatment and surveillance may be instituted. Active treatment, whether for screened or unscreened infants, improves clinical status and long-term survival of CF patients. It is anticipated that new treatments will become available within the next few years, and these will clearly give maximal benefit to young infants if instituted before lung damage is evident. In addition to any hypothetical effects on morbidity and survival, pre-symptomatic diagnosis greatly improves the doctor-parent relationship. Economic arguments may be distorted, but, at best, screening is cost-beneficial, and, at worst, it is cost-neutral. The overwhelming majority of CF professionals and parents universally support neonatal screening, so the onus is therefore on those who oppose screening to prove that their approach offers a superior strategy.     

Why screen for cystic fibrosis? A clinician's view

Cystic fibrosis (CF) is relatively common, serious, and causes progressive lung damage. Clinical diagnosis may be delayed until lung damage has occurred, and infection may start as early as six weeks of life. A well organised screening programme should identify the great majority of affected infants within the first three weeks after birth, which leaves a small time window during which effective preventive treatment and surveillance may be instituted. Active treatment, whether for screened or unscreened infants, improves clinical status and long-term survival of CF patients. It is anticipated that new treatments will become available within the next few years, and these will clearly give maximal benefit to young infants if instituted before lung damage is evident. In addition to any hypothetical effects on morbidity and survival, pre-symptomatic diagnosis greatly improves the doctor-parent relationship. Economic arguments may be distorted, but, at best, screening is cost-beneficial, and, at worst, it is cost-neutral. The overwhelming majority of CF professionals and parents universally support neonatal screening, so the onus is therefore on those who oppose screening to prove that their approach offers a superior strategy.     

Neonatal screening for cystic fibrosis: present and future

Despite there being effective tests for detecting cystic fibrosis (CF) using newborn screening blood samples, screening in neonates has not had universal approval because of uncertainty about its benefits. After up to 18 y experience, at a recent conference in Caen several aspects attracted universal agreement. There is still major delay in clinical diagnosis after the onset of symptoms. There is short-term benefit in early diagnosis by screening, with reduced morbidity in the first 2 y, evidence of significant nutritional benefits up to the age of 10 y, and probable respiratory benefit over this time frame. There is great potential for research into treatment modalities and no evidence of significant psychological harm to CF babies from early diagnosis. With a screening protocol that includes a DNA test there is some unwanted carrier detection and careful genetic counselling is needed. There is no evidence yet that screening will extend the life of CF patients, so some doubts remain as to its overall effectiveness, and there have been no good studies on comparative costs in screened and unscreened cohorts. Even so, the weight of evidence suggests very worthwhile advantages for screened babies and their families. Because of this, it is unlikely that further trials will take place. It may be that the onus now is on those who do not support screening to justify this stance to parents who may favour it.     

Neonatal screening for cystic fibrosis: present and future

Despite there being effective tests for detecting cystic fibrosis (CF) using newborn screening blood samples, screening in neonates has not had universal approval because of uncertainty about its benefits. After up to 18 y experience, at a recent conference in Caen several aspects attracted universal agreement. There is still major delay in clinical diagnosis after the onset of symptoms. There is short-term benefit in early diagnosis by screening, with reduced morbidity in the first 2 y, evidence of significant nutritional benefits up to the age of 10 y, and probable respiratory benefit over this time frame. There is great potential for research into treatment modalities and no evidence of significant psychological harm to CF babies from early diagnosis. With a screening protocol that includes a DNA test there is some unwanted carrier detection and careful genetic counselling is needed. There is no evidence yet that screening will extend the life of CF patients, so some doubts remain as to its overall effectiveness, and there have been no good studies on comparative costs in screened and unscreened cohorts. Even so, the weight of evidence suggests very worthwhile advantages for screened babies and their families. Because of this, it is unlikely that further trials will take place. It may be that the onus now is on those who do not support screening to justify this stance to parents who may favour it.     

Protracted neonatal hypertrypsinogenaemia, normal sweat chloride, and cystic fibrosis

The cystic fibrosis (CF) clinical spectrum has greatly expanded in the past few years, including atypical forms with low sweat chloride concentrations. Two cases are presented which suggest that children detected by neonatal CF screening whose trypsinogen concentrations are still raised by the second month of age could, despite a negative sweat test, be affected by an atypical CF with fully expressed pulmonary involvement.     

Protracted neonatal hypertrypsinogenaemia, normal sweat chloride, and cystic fibrosis.

The cystic fibrosis (CF) clinical spectrum has greatly expanded in the past few years, including atypical forms with low sweat chloride concentrations. Two cases are presented which suggest that children detected by neonatal CF screening whose trypsinogen concentrations are still raised by the second month of age could, despite a negative sweat test, be affected by an atypical CF with fully expressed pulmonary involvement.