Newborn screening for cystic fibrosis: ensuring more good than harm

Abstract

“We must work to ensure that every child has an optimal chance for a healthy start in life.”—Surgeon General David Satcher,Commissioned Corps Bulletin, USPHSFebruary 2001 Cystic fibrosis (CF) has many characteristic signs and symptoms, but establishing a timely diagnosis remains a major challenge.1.Cystic Fibrosis Foundation, Patient Registry 2001 Annual Report, Bethesda, Maryland.Google Scholar, 2.Farrell P.M. Mischler E.H. Newborn screening for cystic fibrosis.Adv Pediatr. 1992; 39: 31-64Google Scholar, 3.Farrell P.M. Improving the health of patients with cystic fibrosis through newborn screening.Adv Pediatr. 2000; 47: 79-115PubMed Google Scholar, 4.Lai H.C. Kosorok M.R. Laxova A. Makholm L.M. Farrell P.M. Delayed diagnosis of US females with cystic fibrosis.Am J Epidemiol. 2002; 156: 165-173Crossref PubMed Scopus (57) Google Scholar With conventional methods of identification, children with CF often have symptoms for months or years before definitive therapy is begun.2.Farrell P.M. Mischler E.H. Newborn screening for cystic fibrosis.Adv Pediatr. 1992; 39: 31-64Google Scholar, 3.Farrell P.M. Improving the health of patients with cystic fibrosis through newborn screening.Adv Pediatr. 2000; 47: 79-115PubMed Google Scholar About half of these patients have severe malnutrition or chronic lung disease at diagnosis.4.Lai H.C. Kosorok M.R. Laxova A. Makholm L.M. Farrell P.M. Delayed diagnosis of US females with cystic fibrosis.Am J Epidemiol. 2002; 156: 165-173Crossref PubMed Scopus (57) Google Scholar, 5.Lai H.C. Kosorok M.R. Sondel S.A. Chen S.T. FitzSimmons S.C. Green C.G. et al.Growth status in children with cystic fibrosis based on the National Cystic Fibrosis Patient Registry data: evaluation of various criteria used to identify malnutrition.J Pediatr. 1998; 132: 478-485Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar Because these delays have not decreased with decades of professional and public education, the CF community has long searched for methods to identify affected children earlier.6.Shwachman H. Redmond A. Khaw K.T. Studies in cystic fibrosis: report of 130 patients diagnosed under 3 months of age over a 20-year period.Pediatrics. 1970; 46: 335-343PubMed Google Scholar, 7.Farrell P.M. Fost N.F. Prenatal screening for cystic fibrosis: where are we now?.J Pediatr. 2002; 141: 758-763Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 8.Cadman D. Chambers L. Feldman W. Sackett D. Assessing the effectiveness of community screening programs.JAMA. 1984; 251: 1580-1585Crossref PubMed Scopus (93) Google Scholar After favorable results from the Wisconsin CF Neonatal Screening Project3.Farrell P.M. Improving the health of patients with cystic fibrosis through newborn screening.Adv Pediatr. 2000; 47: 79-115PubMed Google Scholar, 9.Farrell P.M. Kosorok M.R. Rock M.J. Laxova A. Zeng L. Lai H.C. et al.Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth.Pediatrics. 2001; 107: 1-12Crossref PubMed Scopus (395) Google Scholar and other studies,10.Waters D.L. Wilcken B. Irwig L. Van Asperen P. Mellis C. Simpson J.M. et al.Clinical outcomes of newborn screening for cystic fibrosis.Arch Dis Child Fetal Neonatal Ed. 1999; 80: 1-7Crossref Scopus (146) Google Scholar, 11.Dankert-Roelse J.E. te Meerman G.J. Long-term prognosis of patients with cystic fibrosis in relation to early detection by neonatal screening in a cystic fibrosis centre.Thorax. 1995; 50: 712-718Crossref PubMed Scopus (121) Google Scholar, 12.Siret D. Bretaudeau G. Branger B. Dabadie A. Dagorne M. David V. et al.Comparing the clinical evolution of cystic fibrosis (CF) screened neonatally to that of CF diagnosed from clinical symptoms: a 10-years retrospective study in a French region (Brittany).Pediatr Pulmonol. 2003; 35: 342-349Crossref PubMed Scopus (85) Google Scholar Farrell3.Farrell P.M. Improving the health of patients with cystic fibrosis through newborn screening.Adv Pediatr. 2000; 47: 79-115PubMed Google Scholar asserted that “the burden of proof is on those who argue against CF neonatal screening.” Since then, examination of outcome data has suggested that screening has the potential for both benefit and harm. Historically, political forces have often pushed for the rapid implementation of screening programs, sometimes resulting in troubling biomedical or psychosocial complications. Clearly, it would be best to avoid such problems during implementation of CF neonatal screening, especially given the likely appearance of many more screening technologies from the Human Genome Project. We have written this Commentary to inform programs that are now implementing or considering CF neonatal screening, especially those who are still unsure about the associated benefits and risks. Cystic fibrosis is caused by mutations such as ΔF508 in the CF transmembrane conductance regulator (CFTR) gene, leading to defective chloride channel functioning13.Welsh M.J. Tsui L. Boat T.F. Beaudet A.L. Cystic fibrosis.in: Shriver C.R. Baudert A.L. Sly W.S. The metabolic and molecular bases of inherited disease. 17th ed. McGraw-Hill, New York1995: 3799-3876Google Scholar and the classic clinical triad of pancreatic insufficiency, chronic suppurative pulmonary disease, and salt loss in sweat. Gastrointestinal disease can develop in utero in the second trimester and lead to meconium ileus in ∼20% of newborns with CF.14.Waters D.L. Dorney S.F.A. Gaskin K.J. Gruca M.A. O'Halloran M. Wilcken B. Pancreatic function in infants identified as having cystic fibrosis in a neonatal screening program.N Engl J Med. 1990; 322: 303-308Crossref PubMed Scopus (115) Google Scholar Potentially lethal protein-energy malnutrition develops in some infants.15.Lai H.C. Farrell P.M. Nutrition and cystic fibrosis.in: Rock C. Monsen E. Nutrition in the prevention and treatment of disease. Academic Press, New York2001: 715-727Google Scholar By 4 years of age, ∼85% of patients have some degree of malabsorption.9.Farrell P.M. Kosorok M.R. Rock M.J. Laxova A. Zeng L. Lai H.C. et al.Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth.Pediatrics. 2001; 107: 1-12Crossref PubMed Scopus (395) Google Scholar, 14.Waters D.L. Dorney S.F.A. Gaskin K.J. Gruca M.A. O'Halloran M. Wilcken B. Pancreatic function in infants identified as having cystic fibrosis in a neonatal screening program.N Engl J Med. 1990; 322: 303-308Crossref PubMed Scopus (115) Google Scholar, 15.Lai H.C. Farrell P.M. Nutrition and cystic fibrosis.in: Rock C. Monsen E. Nutrition in the prevention and treatment of disease. Academic Press, New York2001: 715-727Google Scholar Regardless of nutritional status, excessive salt loss in sweat can be fatal for patients exposed to moderate heat or during prolonged hot weather. The pulmonary aspects of CF vary widely in age of onset and rate of progression and are often the most difficult to treat.16.Davis P.B. Drumm M. Konstan M.W. State of the art. Cystic fibrosis.Am J Respir Crit Care Med. 1996; 154: 1229-1256Crossref PubMed Scopus (822) Google Scholar Newborns with CF have histologically normal respiratory systems, but within a few months the epithelial chloride channel defect may lead to abnormal respiratory secretions, bronchopulmonary infection, and airway obstruction. Most patients with CF develop chronic infections with unusual respiratory pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa (Pa). The severity of lung disease generally determines prognosis, but other factors include sex, genotype and the impact of malnutrition and Pa infection.17.Wood R.E. Prognosis.in: Verlag C.T. Cystic fibrosis. Thieme-Stratton, New York1984: 434-460Google Scholar, 18.West S. Zeng L. Lee B.L. Kosorok M.R. Laxova A. Rock M.J. et al.Respiratory infections with Pseudomonas aeruginosa in children with cystic fibrosis: early detection by serology and assessment of risk factors.JAMA. 2002; 287: 2958-2967Crossref PubMed Scopus (162) Google Scholar, 19.Kosorok M.R. Zeng L. West S. Rock M.J. Splaingard M.L. Laxova A. et al.Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition.Pediatr Pulmonol. 2001; 32: 277-287Crossref PubMed Scopus (338) Google Scholar, 20.Mérelle M.E. Schouten J.P. Gerritsen J. Dankert-Roelse J.E. Infuence of neonatal screening and centralized treatment on long-term clinical outcome and survival of CF patients.Eur Respir J. 2001; 18: 306-315Crossref PubMed Scopus (109) Google Scholar Although the median survival of patients in the United States seems to have plateaued at ∼35 years, various projections suggest that those diagnosed early may have a lifespan exceeding 50 years.20.Mérelle M.E. Schouten J.P. Gerritsen J. Dankert-Roelse J.E. Infuence of neonatal screening and centralized treatment on long-term clinical outcome and survival of CF patients.Eur Respir J. 2001; 18: 306-315Crossref PubMed Scopus (109) Google Scholar, 21.Lai HC, Cheng Y, Cho H, Kosorok MR, Farrell PM. Relationship between initial disease presentation, lung disease outcomes and survival in patients with cystic fibrosis. Am J Epidemiol. In PressGoogle Scholar The traditional method of CF diagnosis is the “sweat test,” which uses pilocarpine iontophoresis to produce sweat for chloride analysis. Sweat chloride concentrations in patients with CF generally exceed 60 mEq/L, although values as low as 30 mEq/L are consistent with the diagnosis in children.22.Farrell P.M. Koscik R.E. Sweat chloride concentrations in infants homozygous or heterozygous for F508 cystic fibrosis.J Pediatr. 1996; 97: 524-528Google Scholar Unfortunately, the sweat test is expensive23.Lee D.S. Rosenberg M.A. Peterson A. Makholm L. Hoffman G. Laessig R.H. et al.Analysis of the cost of diagnosing cystic fibrosis with a newborn screening program.J Pediatr. 2003; 142: 617-623Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar and is only effective when the clinician has a high enough index of suspicion to order it. Delays in obtaining a sweat test are common. The average age of diagnosis in the United States is about 3 years of age,1.Cystic Fibrosis Foundation, Patient Registry 2001 Annual Report, Bethesda, Maryland.Google Scholar and many children with CF develop chronic sequelae by this time.4.Lai H.C. Kosorok M.R. Laxova A. Makholm L.M. Farrell P.M. Delayed diagnosis of US females with cystic fibrosis.Am J Epidemiol. 2002; 156: 165-173Crossref PubMed Scopus (57) Google Scholar, 5.Lai H.C. Kosorok M.R. Sondel S.A. Chen S.T. FitzSimmons S.C. Green C.G. et al.Growth status in children with cystic fibrosis based on the National Cystic Fibrosis Patient Registry data: evaluation of various criteria used to identify malnutrition.J Pediatr. 1998; 132: 478-485Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar These delays can be disparately greater for certain populations, including females, children with limited access to care because of economic or geographic factors, and in certain ethnic groups due to the myth that CF is solely a disease of Caucasians.4.Lai H.C. Kosorok M.R. Laxova A. Makholm L.M. Farrell P.M. Delayed diagnosis of US females with cystic fibrosis.Am J Epidemiol. 2002; 156: 165-173Crossref PubMed Scopus (57) Google Scholar Other reasons for delays include the relative rarity of new diagnoses of CF in individual practices and the fact that many sweat tests are typically ordered for every patient actually found to have CF.23.Lee D.S. Rosenberg M.A. Peterson A. Makholm L. Hoffman G. Laessig R.H. et al.Analysis of the cost of diagnosing cystic fibrosis with a newborn screening program.J Pediatr. 2003; 142: 617-623Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Thus, although sweat testing remains the “gold standard” method for diagnosis of CF,24.Rosenstein B.J. The diagnosis of cystic fibrosis: a consensus statement.J Pediatr. 1998; 132 (for the Cystic Fibrosis Foundation Consensus Panel): 589-595Abstract Full Text Full Text PDF PubMed Scopus (894) Google Scholar its use coupled with clinical judgment is suboptimal with regard to overall population health and the medical outcomes of many patients. Recognizing the limitations of sweat testing and potential value of early diagnosis, Shwachman et al advocated for screening as early as 1970.6.Shwachman H. Redmond A. Khaw K.T. Studies in cystic fibrosis: report of 130 patients diagnosed under 3 months of age over a 20-year period.Pediatrics. 1970; 46: 335-343PubMed Google Scholar Initial attempts to test meconium for evidence of CF were unsuccessful. In 1979, Crossly et al25.Crossley J.R. Smith P.A. Edgar B.W. Gluckman P.K. Elliott R.B. Neonatal screening for cystic fibrosis, using immunoreactive trypsin assay in dried blood spots.Clin Chim Acta. 1981; 113: 111-121Crossref PubMed Scopus (4) Google Scholar showed that dried newborn blood specimens could be tested for immunoreactive trypsinogen (IRT) levels, which are increased even in patients with intact pancreatic function. Initial findings from Australia26.Wilcken B. Wiley V. Sherry G. Bayliss U. Neonatal screening for cystic fibrosis: a composition of two strategies for case detection in 1 million babies.J Pediatr. 1995; 127: 965-970Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar and Colorado27.Hammond K.B. Abman S.H. Sokol R.J. Accurso F.J. Efficacy of statewide neonatal screening for cystic fibrosis by assay of trypsinogen concentrations.N Engl J Med. 1991; 325: 769-774Crossref PubMed Scopus (141) Google Scholar were promising, but a Cystic Fibrosis Foundation (CFF) consensus group recommended more research.28.Ad Hoc Committee Task Force on Neonatal Screening, Cystic Fibrosis Foundation Neonatal screening for cystic fibrosis: position paper.Pediatrics. 1983; 72: 741-745PubMed Google Scholar Plans already underway for a randomized controlled trial of neonatal screening in Wisconsin were then finalized, with funding from the CFF and the National Institutes of Health. After discovery of the CFTR gene in 1989, Wisconsin and other regions implemented a second tier of testing using DNA (ΔF508) analysis of specimens found positive on the IRT assay.29.Gregg R.G. Simantel A. Farrell P.M. Koscik R. Kosorok M.R. Laxova A. et al.Newborn screening for cystic fibrosis in Wisconsin: comparison of biochemical and molecular methods.Pediatr. 1997; 99: 819-824Crossref PubMed Scopus (111) Google Scholar, 30.Farrell P.M. Aronson R.A. Hoffman Laessig R.H. Newborn screening for cystic fibrosis in Wisconsin: first application of population-based molecular genetics testing.Wisc Med J. 1991; 93: 415-421Google Scholar The Wisconsin study has since become the largest prospective pediatric research project since the 1954 polio vaccine field trials. Modern CF screening methods utilize analysis of dried blood specimens collected at about 1 to 3 days of age using a heel stick and the “Guthrie card.”31.Bobadilla J.L. Farrell M.H. Farrell P.M. Applying CFTR molecular genetics to facilitate the diagnosis of cystic fibrosis through screening.Adv Pediatr. 2002; 49: 131-190PubMed Google Scholar Specimen cards are mailed to regional laboratories, most of which are organized and funded by government agencies such as state divisions of health. Unfortunately, screening program policies and procedures vary widely, especially in practices for follow-up and communication of results.32.Farrell M.H. Certain L.K. Farrell P.M. Genetic counseling and other risk communication services by newborn screening programs.Arch Pediatr Adolesc Med. 2001; 155: 120-126Crossref PubMed Scopus (57) Google Scholar In fact, the US programs have never had national policies, although the Centers for Disease Control and Prevention has recently assumed a role in promoting quality monitoring of laboratory procedures. IRT analysis is the first step for all CF neonatal screening tests (Table I) and the sole method in some regions. A single IRT test, or the IRT/IRT combination, is 85% to 90% sensitive2.Farrell P.M. Mischler E.H. Newborn screening for cystic fibrosis.Adv Pediatr. 1992; 39: 31-64Google Scholar, 27.Hammond K.B. Abman S.H. Sokol R.J. Accurso F.J. Efficacy of statewide neonatal screening for cystic fibrosis by assay of trypsinogen concentrations.N Engl J Med. 1991; 325: 769-774Crossref PubMed Scopus (141) Google Scholar, 33.Rock M.J. Mischler E.H. Farrell P.M. Bruns W.T. Hassemer D.J. Laessig R.H. et al.Newborn screening for cystic fibrosis is complicated by the age-related decline in immunoreactive trypsinogen levels.Pediatrics. 1990; 85: 1001-1007PubMed Google Scholar and is associated with a relatively large number of false-positive results. With both methods, infants who have positive IRT screens are referred for a sweat test to determine which infants actually do have CF. Several programs now use DNA-based testing in place of a second IRT.31.Bobadilla J.L. Farrell M.H. Farrell P.M. Applying CFTR molecular genetics to facilitate the diagnosis of cystic fibrosis through screening.Adv Pediatr. 2002; 49: 131-190PubMed Google Scholar Originally, ΔF508 was the sole mutation for these tests, but some regions have begun implementing CFTR multimutational analysis.31.Bobadilla J.L. Farrell M.H. Farrell P.M. Applying CFTR molecular genetics to facilitate the diagnosis of cystic fibrosis through screening.Adv Pediatr. 2002; 49: 131-190PubMed Google Scholar Specimens with the highest IRT results go on to DNA testing, although the specific “cutoff” value varies from the highest 1% to 5% of IRT results.29.Gregg R.G. Simantel A. Farrell P.M. Koscik R. Kosorok M.R. Laxova A. et al.Newborn screening for cystic fibrosis in Wisconsin: comparison of biochemical and molecular methods.Pediatr. 1997; 99: 819-824Crossref PubMed Scopus (111) Google Scholar, 30.Farrell P.M. Aronson R.A. Hoffman Laessig R.H. Newborn screening for cystic fibrosis in Wisconsin: first application of population-based molecular genetics testing.Wisc Med J. 1991; 93: 415-421Google Scholar, 31.Bobadilla J.L. Farrell M.H. Farrell P.M. Applying CFTR molecular genetics to facilitate the diagnosis of cystic fibrosis through screening.Adv Pediatr. 2002; 49: 131-190PubMed Google Scholar Even in cases when the DNA analysis is negative, a very high IRT is still considered suspicious for CF. In the Wisconsin program,30.Farrell P.M. Aronson R.A. Hoffman Laessig R.H. Newborn screening for cystic fibrosis in Wisconsin: first application of population-based molecular genetics testing.Wisc Med J. 1991; 93: 415-421Google Scholar infants with an IRT >180 ng/mL are “recommended for sweat testing.” All of these methods are potentially less expensive than the traditional method of diagnosis.2.Farrell P.M. Mischler E.H. Newborn screening for cystic fibrosis.Adv Pediatr. 1992; 39: 31-64Google Scholar, 23.Lee D.S. Rosenberg M.A. Peterson A. Makholm L. Hoffman G. Laessig R.H. et al.Analysis of the cost of diagnosing cystic fibrosis with a newborn screening program.J Pediatr. 2003; 142: 617-623Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar There are several advantages of two-tier IRT/DNA analysis over IRT testing alone: (1) affected infants are identified earlier, especially when a DNA-based diagnosis obviates the need for a sweat test; (2) it provides a better sensitivity, specificity, and positive predictive value than IRT alone29.Gregg R.G. Simantel A. Farrell P.M. Koscik R. Kosorok M.R. Laxova A. et al.Newborn screening for cystic fibrosis in Wisconsin: comparison of biochemical and molecular methods.Pediatr. 1997; 99: 819-824Crossref PubMed Scopus (111) Google Scholar; (3) the DNA step also reduces the number of false-positive results among African American infants or newborns with low APGAR scores34.Rock M.J. Mischler E.H. Farrell P.M. Bruns W.T. Hassemer D.J. Laessig R.H. Immunoreactive trypsinogen screening for cystic fibrosis: characterization of infants with a false-positive screening test.Pediatr Pulmonol. 1989; 6: 42-48Crossref PubMed Scopus (62) Google Scholar; (4) the two-tier strategy avoids arranging for repeat specimen collection (as is done with IRT/IRT screening), saving time and money, as well as “lost” cases27.Hammond K.B. Abman S.H. Sokol R.J. Accurso F.J. Efficacy of statewide neonatal screening for cystic fibrosis by assay of trypsinogen concentrations.N Engl J Med. 1991; 325: 769-774Crossref PubMed Scopus (141) Google Scholar; and (5) DNA testing allows identification of some heterozygous infants whose families may benefit from genetic counseling.Table IMethods used for CF neonatal screening∗A fifth method has also been proposed to use DNA analysis (either ΔF508 or CFTR multimutation) on all infants, but implementation is unlikely because of expense and heterozygote detection.Testing methodDescriptionFollow-up sweat testingIRTIRT analysis of the initial specimen obtained at 24-72 hours of lifeRequiredIRT/IRTIRT analysis of the initial specimen obtained at 24-72 hours of life plus repeat analysis (to reduce false-positive results) on a routine recall specimenRequiredIRT/DNA (ΔF508)†Some programs have recently added a third tier with a follow-up IRT determination if the DNA analysis is negative (ie, IRT/DNA/IRT), but the value of this strategy is uncertain.IRT analysis of the initial specimen, with positive specimens subsequently tested for the ΔF508 mutationMay not be required if ΔF508/ΔF508is deletedIRT/DNA (CFTR)†Some programs have recently added a third tier with a follow-up IRT determination if the DNA analysis is negative (ie, IRT/DNA/IRT), but the value of this strategy is uncertain.IRT analysis of the initial specimen, with positive specimens subsequently tested for a panel of the most common mutations in the geographic areaMay not be required∗ A fifth method has also been proposed to use DNA analysis (either ΔF508 or CFTR multimutation) on all infants, but implementation is unlikely because of expense and heterozygote detection.† Some programs have recently added a third tier with a follow-up IRT determination if the DNA analysis is negative (ie, IRT/DNA/IRT), but the value of this strategy is uncertain. Open table in a new tab The first benefit observed in studies of neonatal screening was a more rapid referral to an accredited CF center, with high-quality respiratory, nutritional, and genetic counseling services.20.Mérelle M.E. Schouten J.P. Gerritsen J. Dankert-Roelse J.E. Infuence of neonatal screening and centralized treatment on long-term clinical outcome and survival of CF patients.Eur Respir J. 2001; 18: 306-315Crossref PubMed Scopus (109) Google Scholar Although referrals in the Wisconsin trial were prompted by the study protocol itself, even the opportunity for early referral cannot be proactively assured without screening. In addition, the opportunity to participate in trials of early intervention cannot occur without early diagnosis. The most consistently observed benefits have been nutritional. In the Wisconsin trial, infants diagnosed with CF through screening were more likely to have normal height and weight measures than those identified through traditional methods, after many experienced prolonged malnutrition.3.Farrell P.M. Improving the health of patients with cystic fibrosis through newborn screening.Adv Pediatr. 2000; 47: 79-115PubMed Google Scholar, 9.Farrell P.M. Kosorok M.R. Rock M.J. Laxova A. Zeng L. Lai H.C. et al.Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth.Pediatrics. 2001; 107: 1-12Crossref PubMed Scopus (395) Google Scholar Similar findings were observed in Australia10.Waters D.L. Wilcken B. Irwig L. Van Asperen P. Mellis C. Simpson J.M. et al.Clinical outcomes of newborn screening for cystic fibrosis.Arch Dis Child Fetal Neonatal Ed. 1999; 80: 1-7Crossref Scopus (146) Google Scholar and France.12.Siret D. Bretaudeau G. Branger B. Dabadie A. Dagorne M. David V. et al.Comparing the clinical evolution of cystic fibrosis (CF) screened neonatally to that of CF diagnosed from clinical symptoms: a 10-years retrospective study in a French region (Brittany).Pediatr Pulmonol. 2003; 35: 342-349Crossref PubMed Scopus (85) Google Scholar Head circumference values were also significantly higher in the Wisconsin trial screened group compared with the standard diagnosis group.9.Farrell P.M. Kosorok M.R. Rock M.J. Laxova A. Zeng L. Lai H.C. et al.Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth.Pediatrics. 2001; 107: 1-12Crossref PubMed Scopus (395) Google Scholar Since these observations, differences in growth and nutritional status have been observed in children as old as 10 to 15 years.3.Farrell P.M. Improving the health of patients with cystic fibrosis through newborn screening.Adv Pediatr. 2000; 47: 79-115PubMed Google Scholar, 9.Farrell P.M. Kosorok M.R. Rock M.J. Laxova A. Zeng L. Lai H.C. et al.Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth.Pediatrics. 2001; 107: 1-12Crossref PubMed Scopus (395) Google Scholar In addition, screening allows prevention of prolonged deficiencies of micronutrients such as vitamin E and the resulting complications, such as hemolytic anemia35.Wilfond B.S. Farrell P.M. Severe hemolytic anemia associated with vitamin E deficiency in infants with cystic fibrosis.Clin Pediatr. 1994; 33: 2-7Crossref PubMed Scopus (49) Google Scholar and abnormalities in cognitive function.36.Koscik RL, Farrell PM, Kosorok MR, Zaremba KM, Laxova A, Lai HC, et al. Cognitive function of children with cystic fibrosis: deleterious effect of malnutrition. Pediatrics. In PressGoogle Scholar The only potential risk of screening related to nutritional care is intestinal stricture, which has been rare in young children, but may occur when excessive dosages of pancreatic microsphere enzymes are consumed.37.Lloyd-Still J.D. Cystic fibrosis and colonic strictures: a new iatrogenic disease.J Clin Gastroenterol. 1995; 21 ([editorial]): 2-5Crossref PubMed Scopus (24) Google Scholar The pulmonary benefits of CF neonatal screening, anticipated intuitively for many years,6.Shwachman H. Redmond A. Khaw K.T. Studies in cystic fibrosis: report of 130 patients diagnosed under 3 months of age over a 20-year period.Pediatrics. 1970; 46: 335-343PubMed Google Scholar have been more challenging to establish because of the variable pattern and age of onset of lung disease, the difficulty in quantification of pediatric lung disease, and variations in genotypic and environmental influences. Observational studies from Australia,10.Waters D.L. Wilcken B. Irwig L. Van Asperen P. Mellis C. Simpson J.M. et al.Clinical outcomes of newborn screening for cystic fibrosis.Arch Dis Child Fetal Neonatal Ed. 1999; 80: 1-7Crossref Scopus (146) Google Scholar the Netherlands,11.Dankert-Roelse J.E. te Meerman G.J. Long-term prognosis of patients with cystic fibrosis in relation to early detection by neonatal screening in a cystic fibrosis centre.Thorax. 1995; 50: 712-718Crossref PubMed Scopus (121) Google Scholar and France12.Siret D. Bretaudeau G. Branger B. Dabadie A. Dagorne M. David V. et al.Comparing the clinical evolution of cystic fibrosis (CF) screened neonatally to that of CF diagnosed from clinical symptoms: a 10-years retrospective study in a French region (Brittany).Pediatr Pulmonol. 2003; 35: 342-349Crossref PubMed Scopus (85) Google Scholar suggest better outcomes in screened groups compared with various CF patients diagnosed conventionally. Unfortunately, these studies could have been affected by selection bias and lack of systematic or controlled respiratory care. The randomized design of the Wisconsin trial avoided these problems but encountered confounders and unexpectedly mild pulmonary dysfunction in both the screened and standard diagnosis (control) groups.38.Farrell P.M. Li Z. Kosorok M.R. Laxova A. Green C.G. Collins J. et al.Longitudinal evaluation of bronchopulmonary disease in children with cystic fibrosis.Pediatr Pulmonol. 2003; 36: 1-11Crossref PubMed Scopus (89) Google Scholar, 39.Farrell P.M. Li Z. Kosorok M.R. Laxova A. Green C.G. Collins J. et al.Bronchopulmonary disease in children with cystic fibrosis after early or delayed diagnosis.Am J Respir Crit Care Med. 2003; 168: 1100-1108Crossref PubMed Scopus (117) Google Scholar Quantitative scoring of chest radiographs in Wisconsin revealed a mixed picture; the scores were significantly better at the time of diagnosis in the screened group, but became similar and then worse once Pa infections developed in the screened patients.39.Farrell P.M. Li Z. Kosorok M.R. Laxova A. Green C.G. Collins J. et al.Bronchopulmonary disease in children with cystic fibrosis after early or delayed diagnosis.Am J Respir Crit Care Med. 2003; 168: 1100-1108Crossref PubMed Scopus (117) Google Scholar However, chest radiographic observations at diagnosis suggested a potential benefit; half of the control group patients diagnosed at a mean age of 108 weeks had radiographically irreversible lung disease compared with 28% of those diagnosed through screening, ie, half of those with delayed diagnosis had already progressed past the “point of no return”.39.Farrell P.M. Li Z. Kosorok M.R. Laxova A. Green C.G. Collins J. et al.Bronchopulmonary disease in children with cystic fibrosis after early or delayed diagnosis.Am J Respir Crit Care Med. 2003; 168: 1100-1108Crossref PubMed Scopus (117) Google Scholar The risks of presymptomatic diagnosis relative to the respiratory system have only been investigated to a limited extent. Most concerns are related to overly aggressive or inappropriate treatment with antibiotics, aerosol inhalations, and chest physiotherapy (which is an unnecessary burd