Anita Laxova

Nutritional Benefits of Neonatal Screening for Cystic Fibrosis

BACKGROUNDnMany 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.nnnMETHODSnWe 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.nnnRESULTSnThe 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.nnnCONCLUSIONSnNeonatal screening provides the opportunity to prevent malnutrition in infants with cystic fibrosis.

Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition

As part of the ongoing Wisconsin Cystic Fibrosis (CF) Neonatal Screening Project, we had the unique opportunity to study the longitudinal relationship between Pseudomonas aeruginosa (Pa) acquisition and infection and developing lung disease in children with CF. The primary objective was to determine whether acquisition of Pa was associated with a measurable change in the progression of lung disease. Two outcome measures were used to study 56 patients who were diagnosed through newborn screening: 1) Wisconsin additive chest radiograph score (WCXR), based on the average of scores from a pulmonologist and a radiologist, and 2) the highest forced expired volume in 1 sec (FEV1)/forced vital capacity (FVC) ratio. We used two measures of Pa acquisition: 1) time of first positive protocol‐determined oropharyngeal (with cough) culture, and 2) the magnitude of antibody titer detected by ELISA assays, using as antigen a crude cell lysate, purified exotoxin A, or an elastase toxoid prepared from three Pa strains. Other predictor variables included age, pancreatic status, height‐for age, and weight‐for‐age‐percentiles.

Cystic Fibrosis Newborn Screening: Impact on Reproductive Behavior and Implications for Genetic Counseling

Objective.u2003To evaluate the impact of newborn screening for cystic fibrosis (CF) on the reproductive knowledge and behavior of CF families and to determine if heterozygote detection with the immunoreactive trypsinogen (IRT) method in conjunction with DNA analysis (IRT/DNA) influences knowledge and attitudes about reproduction in false-positive families. Methods.u2003The Wisconsin CF Neonatal Screening Project investigated 650u2009340 infants from 1985 to 1994 in a comprehensive randomized controlled trial to study both benefits and risks of newborn screening and to determine if early diagnosis would improve the prognosis of children with CF. Assessments of reproductive knowledge, attitudes, and behaviors of 135 families of children diagnosed as having CF in both the early treatment group and control groups were made 3 months after diagnosis using a questionnaire which was completed by 100 families. The same questionnaire was administered 1 year later to evaluate retention of information. It was completed by 71 families. A follow-up assessment tool was also administered in 1994 and responses obtained from 73 families. Knowledge, attitudes, and behavior among false-positive families were also assessed at the time of the sweat test in 206 families who experienced IRT screening and 109 families tested with the IRT/DNA method. Follow-up assessments were completed 1 year later in 106 IRT families and 63 IRT/DNA families. Results.u2003In families with a CF child, 95% initially understood that there was a 1 in 4 risk in subsequent pregnancies, and there was good retention of this information 1 year later. At the 1994 assessment, 52% of families had not yet conceived more children, but 74% of these already had children. In the couples in whom CF was diagnosed in the first child, 70% (95% confidence interval = 54% to 85%) conceived more children. There were 43 subsequent pregnancies in 31 families. Prenatal diagnosis was used by 26% of the families (8/31) for 21% of the pregnancies (9/43). There were 3 pregnancies with CF detected, all of which were carried to term. In the false-positive groups, >95% of families initially understood that their child definitely did not have CF. There was no difference between false-positive IRT and IRT/DNA groups, and the information was retained at 1 year. Follow-up assessment 1 year after negative sweat tests revealed that 7% of the IRT and 10% of the IRT/DNA families still thought about the results often or constantly. When asked whether the experience of screening affected feelings about having more children, an affirmative response was obtained in 4% of IRT families but in 17% of IRT/DNA families. One year later, more than half of the false-positive IRT/DNA families did not understand that they were at increased risk of having a child with CF. Conclusions.u2003We conclude that CF neonatal screening does not have a significant impact on the reproductive behavior of most families and that prenatal diagnosis is not used by the majority of CF families. IRT/DNA testing experiences seem to affect attitudes about having more children, and some parents are confused about the implications of the results, even with genetic counseling. However, persistent concerns about the sweat test result are limited. Questions raised by this study confirm the need for more research regarding the process of genetic counseling and its impact on reproductive attitudes and behavior in the newborn screening setting.

Genetic counseling and neonatal screening for cystic fibrosis: an assessment of the communication process.

Objective. To assess the effectiveness of communication between health care providers (physicians, nurses, genetic counselors) in Wisconsin and parents of children identified as heterozygote carriers for cystic fibrosis (CF) in the routine Wisconsin Newborn Screening Program that was implemented using trypsinogen/DNA testing. Methods. Routine CF neonatal screening, implemented in July 1994, involved a statewide system that recommended but did not mandate follow-up sweat tests at 1 of the Wisconsins 2 certified CF centers. The Wisconsin Division of Health sent requests to participate to the parents of 483 infants identified as CF carriers between July 1994 and December 1997. Of the 483 parents, 183 agreed to participate and were asked to complete a questionnaire assessing their CF newborn screening experiences and their knowledge of CF genetics and any changes they made in their reproductive behavior as a result of this knowledge. Follow-up telephone interviews by a genetic counselor were attempted within 1 year for those completing the questionnaire. Results. Within 4 months after the mailing, 138 of 183 (75%) parents completed the questionnaire. Subsequently, 123 of the 138 responders (89%) were contacted and interviewed by telephone. We learned that 67.6% of parents recalled receiving genetic counseling, but 32.4% of parents apparently did not participate in a risk communication session. When asked, “Who performed the genetic counseling?” parents indicated that their communication was with physicians in 8% of cases, nurses in 12.4%, and certified genetic counselors in 32.8% of cases; 17.5% of parents did not recall who performed the genetic counseling and 29.2% of parents indicated they did not receive genetic counseling. Based on the 138 responses, it was found that 88.3% of parents understood that their child was a carrier for CF, but 15.4% of parents were unsure whether being a carrier could cause illness. In addition, 12.4% of parents were unsure whether at least 1 of them (parents) was a carrier of the CF gene. Only 57% of parents knew there was a 1 in 4 chance that their child could have a child with CF if he or she reproduced with another carrier of the CF gene. Statistically significant differences were noted when comparing the frequency of correct responses between parents who received genetic counseling and parents who had not. The frequency of accurate responses did not depend on which health care professional provided the genetic counseling. Comparing responses of parents who were seen at a certified CF center with parents seen at other community hospitals and clinics revealed significant differences in the frequency of correct responses, with the former group showing a higher percentage of correct responses. Telephone interviews revealed that 11.4% of parents were unaware that their child was a carrier for CF and that 54.5% wished they had more information made available to them at the time of the initial positive newborn screen result, before the definitive sweat test. Also, 13.8% of parents recommended that community physicians be better informed of the details and implications of positive screening results for CF. Conclusion. Genetic counseling is imperative for the success of newborn screening for CF and other congenital diseases. With the completion of the Human Genome Project, more molecular screening for childhood disease is bound to enter the clinical arena. Based on our findings, efforts must be made to ensure that newborn screening programs have the means and the methods to communicate newborn screening results effectively to families. In addition, both the general public and community health providers must be better informed of the implications of all newborn screening results. Additional research is needed to determine whether there are communication styles and approaches that are better suited to counseling parents regarding newborn screening results.

Reproducibility of a scoring system for computed tomography scanning in cystic fibrosis.

Introduction Computerized tomography (CT) scanning shows promise as an outcome surrogate for cystic fibrosis (CF) lung disease progression. The scoring system used to convert the CT image to numeric data is an essential determinant of the performance of CT scanning. Methods Three radiologists independently scored 16 high-resolution CT scans performed on children in the Wisconsin CF Neonatal Screening Project. The test scans were selected to provide a broad range of disease severity. The scoring system provided subscores for the presence and severity of 5 findings of CF lung disease. The sum of the subscores provided a total score. The CT scans were then read again by each of the radiologists at least 11 months later. Using Mixed Effects Linear Model Analysis, the sources of error (scan-to-scan variation, interrater variance, and intrarater variance) were calculated. Results For the total score, the scan-to-scan variation was 14.48, interrater variance was 0.28, and intrarater variance was 0.45, with an overall reproducibility of 95%. The square root of scan-to-scan variance, a measure of sensitivity, was 3.81. Evaluation of the subscores showed higher reproducibility for bronchiectasis and hyperinflation (95% and 88%, respectively). The bronchiectasis score was more sensitive than the air-trapping score (1.46 vs. 0.89). Discussion This system was developed to provide a reproducible method that could be used to evaluate the lobar location, severity, and extent of a broad spectrum of CT features of CF lung disease, especially in children. This study demonstrates that the overall score is both sensitive to variation in the severity of lung disease and reproducible.

Nutritional status of patients with cystic fibrosis with meconium ileus: a comparison with patients without meconium ileus and diagnosed early through neonatal screening.

Objective. This study was pursued as an extension of a randomized clinical investigation of neonatal screening for cystic fibrosis (CF). The objective was to determine if CF patients with meconium ileus (MI) were more likely to be malnourished compared with those without MI who were diagnosed during early infancy through neonatal screening. Methodology. Nutritional status was evaluated from early infancy to 13 years of age based on anthropometric, biochemical, and dietary assessments. Results. MI patients (n = 32) were smaller at birth (3117 g compared with 3413 g) and were shorter (22nd percentile compared with 48th percentile) and thinner (24th percentile compared with 49th percentile) compared with non-MI early diagnosed patients (n = 50) up to 13 years of age. Poor growth was particularly evident in 26 MI patients who required surgery for MI (height and weight at the 20th percentile), whereas those treated without surgery (n = 6) showed better height (45th percentile) and weight (37th percentile). Abnormal essential fatty acid profiles were significantly more prevalent in MI compared with non-MI early-diagnosed patients before 3 years of age. Daily intakes of calorie (130% compared with 111% recommended dietary allowances) and protein (339% compared with 279% recommended dietary allowances) were higher but the percentage of fat (37% compared with 38%) and linoleic acid (4.5% compared with 4.7%) in the diet were similar between the two groups. Conclusions. These results demonstrated a clear association of MI with malnutrition in CF. The observed poor growth among our MI patients was not because of poor dietary intakes, but was related to surgical treatment for MI and poor essential fatty acid status. These findings present new challenges regarding the optimal medical treatment and nutritional intervention for CF patients with MI.

Comprehensive analysis of risk factors for acquisition of Pseudomonas aeruginosa in young children with cystic fibrosis

The objective of this study was to identify risk factors of significance for acquisition of Pseudomonas aeruginosa by children with cystic fibrosis (CF). Our working hypothesis is that exposure of infants and young children with CF to older, infected patients increases their risk for acquiring this organism. A special opportunity arose to study this question in detail, as we have been performing a randomized clinical trial of neonatal screening for CF throughout the state of Wisconsin during the period of 1985–1994. Patients were selected for this study based on either early identification through screening or diagnosis by standard methods. A longitudinal protocol employed at Wisconsins two CF Centers includes routine cultures of respiratory secretions and collection of clinical, demographic, and activity information on patients and their families. Previous observations in our trial revealed that one center at an old hospital in an urban location showed a significantly shorter time to acquisition of P. aeruginosafor CF patients followed there. To study the center effect further, we performed statistical analyses using survival curves and stepwise regression analysis of all life history covariates available. The results of these analyses showed that the statistically significant correlations involve the following risk factors: (1) center and old hospital (r = 0.42); (2) center and original physician (r = 0.61); (3) center and exposure to pseudomonas‐positive patients (r = 0.29); and (4) population density and urban location (r = 0.49). The final statistical model demonstrated that increased risk due to aerosol use (odds ratio = 3.45, P = 0.014) and a protective effect associated with education of the mother (odds ratio = 0.81, P = 0.024) were the most significant factors for acquisition of P. aeruginosa. The previously observed center effect was confined to the 1985–1990 interval at the old hospital (odds ratio = 4.43, P < 0.001). We conclude that multiple factors are involved in increasing the risk of young children with CF to acquire P. aeruginosa, and that the observed center effect can best be explained by a combination of factors. These results suggest that facilities and methods used to care for young children with CF can significantly influence their likelihood of acquiring pseudomonas in the respiratory tract. Pediatr Pulmonol. 1998; 26:81–88.

Wisconsin cystic fibrosis chest radiograph scoring system: Validation and standardization for application to longitudinal studies †

This study was designed to achieve a final modeling, validation, and standardization plan for the Wisconsin cystic fibrosis (CF) chest radiographic scoring system. Sixty chest radiographs were selected to reflect a range of severity of lung pathology in children with CF. Seven experienced volunteer raters (three radiologists and four pediatric pulmonologists) from five institutions were recruited to evaluate and score the films. Analysis of scores revealed that the subcomponents of the Wisconsin system showed considerable variation from rater to rater, but reliability assessment indicated satisfactory Cronbachs alpha coefficients (0.83–0.90) among the seven raters. It was found that an additive method of total score computation is significantly more reliable (P < 0.05) than either the original multiplicative model or the traditional Brasfield scoring system. Comparison of radiologists and pulmonologists revealed a marked, systematic difference in scoring with the former group being more conservative in interpretation of abnormalities than the pulmonologists, and some of the raters showing very limited sensitivity.

Severe Hemolytic Anemia Associated With Vitamin E Deficiency in Infants With Cystic Fibrosis: Implications for Neonatal Screening

Three infants are described with cystic fibrosis (CF) and malnutrition leading to severe anemia beginning as early as 6 weeks of age. Laboratory studies demonstrated high reticulocyte counts, negative Coombs tests, abnormal peroxide hemolysis test results, and biochemical evidence of vitamin E deficiency. Oral administration of α-tocopherol resulted in rapid correction of the in vitro hemolysis and improvement of in vivo hematologic indices. Investigation of these patients supports the conclusion that the hemolytic anemia of infancy in CF is caused by vitamin E deficiency and should be treated promptly with 50 IU/day of vitamin E. Because two of the three patients were identified in a CF screening/surveillance program, we can estimate that the frequency of clinically significant anemia in CF infants is 4%. Our observations demonstrate a potential advantage of CF neonatal screening for individual patients susceptible to vitamin E-deficient hemolytic anemia and suggest that confirmatory follow-up diagnostic studies, such as sweat tests, should be performed by 4 to 6 weeks of age.

Association between Mucoid Pseudomonas Infection and Bronchiectasis in Children with Cystic Fibrosis

PURPOSEnTo correlate the severity of bronchiectasis in children with cystic fibrosis with clinical and microbiologic variables in order to clarify risk factors for the development of irreversible lung disease.nnnMATERIALS AND METHODSnAfter institutional review board approval and parental informed consents were obtained, a HIPAA-compliant longitudinal epidemiologic evaluation was performed in patients with cystic fibrosis who were enrolled in the Wisconsin trial of newborn screening from 1985 to 2009. Thin-section chest computed tomography (CT) was used in a prospective cross-sectional design to study patients ranging in age from 6.6 to 17.6 years (mean, 11.5 years). Thin-section CT scores were determined objectively on coded images by multiple raters in a standardized fashion. Microbiologic data were obtained by means of culture of respiratory secretions by using methods for differentiation of Pseudomonas aeruginosa (PA) as either nonmucoid or mucoid.nnnRESULTSnEighty-three percent of patients (68 of 82) showed bronchiectasis of varying severity. Of 12 potential risk factors, only respiratory infection with mucoid PA correlated significantly with bronchiectasis (P = .041).nnnCONCLUSIONnThe severity of bronchiectasis in children with cystic fibrosis is significantly related to respiratory infection with mucoid PA; attempts to prevent bronchiectasis should include reducing exposure to and early eradication of PA.