Nutritional benefits of neonatal screening for cystic fibrosis. Wisconsin Cystic Fibrosis Neonatal Screening Study Group.

BACKGROUND: Many patients with cystic fibrosis are malnourished at the time of diagnosis. Whether newborn screening and early treatment may prevent the development of a nutritional deficiency is not known. METHODS: We compared the nutritional status of patients with cystic fibrosis identified by neonatal screening or by standard diagnostic methods. A total of 650,341 newborn infants were screened by measuring immunoreactive trypsinogen on dried blood spots (from April 1985 through June 1991) or by combining the trypsinogen test with DNA analysis (from July 1991 through June 1994). Of 325,171 infants assigned to an early-diagnosis group, cystic fibrosis was diagnosed in 74 infants, including 5 with negative screening tests. Excluding infants with meconium ileus, we evaluated nutritional status for up to 10 years by anthropometric and biochemical methods in 56 of the infants who received an early diagnosis and in 40 of the infants in whom the diagnosis was made by standard methods (the control group). Pancreatic insufficiency was managed with nutritional interventions that included high-calorie diets, pancreatic-enzyme therapy, and fat-soluble vitamin supplements. RESULTS: The diagnosis of cystic fibrosis was confirmed by a positive sweat test at a younger age in the early-diagnosis group than in the control group (mean age, 12 vs. 72 weeks). At the time of diagnosis, the early-diagnosis group had significantly higher height and weight percentiles and a higher head-circumference percentile (52nd, vs. 32nd in the control group; P=0.003). The early-diagnosis group also had significantly higher anthropometric indexes during the follow-up period, especially the children with pancreatic insufficiency and those who were homozygous for the deltaF508 mutation. CONCLUSIONS: Neonatal screening provides the opportunity to prevent malnutrition in infants with cystic fibrosis.

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

Neonatal screening for cystic fibrosis (CF) has become feasible through analyzing dried blood specimens for immunoreactive trypsinogen (IRT), but the benefits and risks of such a screening program remain to be delineated. This study, a survey of the parents of 104 Wisconsin infants with false-positive IRT tests, showed parents had knowledge deficits about neonatal screening in general, misconceptions about test results, and high levels of anxiety. Parenting behaviors were reportedly unchanged during the usual 3-day waiting period between the news of the abnormal screening test and the diagnostic sweat test. Most, but not all, parents were relieved by negative sweat test results subsequent to the abnormal IRT test. Factors associated with continued parental concern included having less than a high school education and/or having an infant with low Apgar scores. Additionally, those contacted by telephone were more likely to have misinformation and lingering concerns about the presence of CF in their child.

Current issues in neonatal screening for cystic fibrosis and implications of the CF gene discovery.

Many questions remain regarding the efficacy, toxicity, and costs of CF neonatal screening. It would be premature, in our opinion, to implement mass population screening of newborns for CF until the benefits and risks have been fully defined, and an adequate and logistically feasible testing system developed and/or highly effective therapy for CF lung disease becomes available. In addition, the ethical issues described herein need to be resolved. This pertains not only to the CF patient but also the heterozygote carrier. These reservations notwithstanding, the discovery of the CF gene should have a favorable impact both directly and indirectly on neonatal screening for the disease. Mutation analysis coupled to IRT testing seems most attractive at this time, at least on a research basis, but primary molecular diagnostic procedures might supervene in the future, particularly if they are financially feasible.

Newborn screening for cystic fibrosis is complicated by age-related decline in immunoreactive trypsinogen levels.

Detection of elevated levels of immunoreactive trypsinogen (IRT) in dried neonatal blood spots has been used as a screening test for cystic fibrosis. In other cystic fibrosis newborn-screening studies, a sweat chloride test is generally performed only if an infant has a persistent IRT level above a selected cutoff value on both the initial and subsequent specimens. Neither the timing of the second specimen nor the value of the cutoff point for the second specimen has been comprehensively evaluated. In this randomized, controlled study, 145,024 infants were screened in the neonatal period for cystic fibrosis using the 99.8 percentile (180 ng/mL) as the neonatal cutoff point. A total of 129 infants had elevated neonatal IRT levels and had negative results on sweat tests (false-positive by IRT screening). A total of 54 children with cystic fibrosis were identified in the screened and comparison groups. Excluding patients with meconium ileus, 4 infants with cystic fibrosis had neonatal IRT values less than 180 ng/mL, and an additional 9 infants with cystic fibrosis had values decline to less than 180 ng/mL within the first 2 1/2 months of age. The IRT values of infants with and without cystic fibrosis overlapped considerably beyond 30 days of age. These findings suggest that further refinement of cystic fibrosis screening methodology will be necessary to achieve an acceptable sensitivity and specificity.

Immunoreactive trypsinogen screening for cystic fibrosis: characterization of infants with a false-positive screening test.

Blood immunoreactive trypsinogen (IRT) is elevated in newborns with cystic fibrosis (CF) and has been used as a neonatal screening test. However, not only is the benefit of early diagnosis unknown, but also the sensitivity, specificity, and time related decline of IRT values have yet to be comprehensively evaluated. This report describes the characteristics of infants with a false-positive IRT in our experience with CF screening of 87,000 infants. The IRT value was elevated in 92 newborns; 13 had a confirmed diagnosis of CF by quantitative pilocarpine iontophoresis sweat testing, and 79 infants did not have CF and were therefore classified as false positives by IRT screening. In order to test the hypothesis that perinatal stress factors are associated with high neonatal IRT values, we evaluated Apgar scores at 1 and 5 minutes. We found that the scores of false-positive infants were significantly lower (P = 0.0004 and P = 0.0102 at 1 and 5 minutes, respectively), compared with infants in the general population. While perinatal asphyxia as reflected by low Apgar scores is an associated factor accounting for an elevated IRT value, the majority of non-CF newborns with an elevated IRT have normal Apgar scores.

Immune responses to Aspergillus in cystic fibrosis.

Aspergillus fumigatus (Af) is well recognized in its ability to colonize the respiratory tract in cystic fibrosis (CF). Furthermore, a number of the immune responses of the patient with CF to this organism have been characterized, and the immune inflammatory response to Af may result in allergic bronchopulmonary aspergillosis (ABPA). This study evaluated a series of immunologic parameters in 75 patients with CF in order to characterize more fully the spectrum of immune responses of those patients to Af and to clarify the relationship of those responses to the clinical features of ABPA. The patients could be classified into four groups, depending on the clinical and immunologic findings. Eight (10.7%) of the 75 patients had clinical and laboratory evidence of ABPA, including immediate cutaneous reactivity to Af, eosinophilia, elevated total serum IgE, elevated serum IgE-Af or IgG-Af, and precipitating antibody to Af. Ten (13.3%) patients had these features, except that the total serum IgE level was within the normal range. Forty (53.5%) of the patients had no significant criteria for ABPA but had varying immunologic responses to Af, such as immediate cutaneous reactivity to Af in 25 patients and elevated serum IgE-Af and/or IgG-Af in 19 patients. Seventeen (22.7%) patients had no evidence of an immunologic response, as determined by skin testing and serologic assays. The study demonstrated that the response of patients with CF to Af ranges from clinically apparent ABPA to a possible variant of ABPA, to a nondiagnostic group of features consistent with sensitization to Af or to no characteristic immune response.

Allergic bronchopulmonary aspergillosis in cystic fibrosis.

One hundred patients with CF were screened for ABPA. Forty-eight male patients and 52 female patients with age range of 2 to 34 yr (mean 14.2) were studied. Patients were evaluated for skin reactivity and serum precipitating antibodies to Af, predominant sputum organisms, total blood eosinophil levels, total serum IgE, and Af-specific IgE and IgG, as well as abnormalities of pulmonary function and chest x-ray films. Careful evaluation of all patients with CF demonstrated that 10% had features indicative of ABPA, which is another potentially destructive pulmonary disorder. Thus careful evaluation of patients with CF, especially those with asthma, may be rewarding in uncovering a disorder that may slow progression of CF when it is appropriately treated.

A precise technique to localize pulmonary-pleural air leaks.

A bubblegram technique is described for identification of air leaks in persistent pneumothorax by introducing water-soluble contrast medium into the pleural space. The technique proved useful in eight children examined for persistent air leaks.

Quantitative effect of theophylline anhydrous on exercise-induced asthma after maximal physical effort.

The quantitative effects of theophylline anhydrous upon exercise-induced asthma (EIA) were evaluated in asthmatic children. Theophylline inhibits EIA after maximal physical effort, increases tolerance to exercise and exerts a greater inhibitory effect upon larger than smaller airways. Its inhibitory effect seems not to be related to plasma theophylline levels.

Effects of sputum from patients with cystic fibrosis on the activity in vitro of 5 antimicrobial drugs on Pseudomonas aeruginosa.

By in vitro tests on 12 strains of Pseudomonas aeruginosa, sputum from patients with cystic fibrosis sharply increased the minimal bactericidal concentrations of polymyxin B and neomycin. Sputum had a lesser effect on tests with gentamicin and tobramycin and essentially none on tests with carbenicillin.

Test strip meconium screening for cystic fibrosis.

The Boehringer-Mannheim Corporation (BMC) strip test is extremely reliable in indicating an albumin content above 20 mg/gm of dried meconium. All infants born during one year in 14 Milwaukee area hospitals were tested. Of 16,224 newborns, two were diagnosed correctly as suffering from cystic fibrosis and two were missed. False-positive tests were obtained in 0.9% of infants (prematurity, melena, gastroschisis, and intrauterine infection). The strip test is, at present, the best available but not the perfect screening method for cystic fibrosis.