Inhaled alpha 1 -proteinase inhibitor therapy in patients with cystic fibrosis

Inhaled alpha1-proteinase inhibitor (PI) is known to reduce neutrophil elastase burden in some patients with CF. This phase 2a study was designed to test inhaled Alpha-1 HC, a new aerosolized alpha1-PI formulation, in CF patients

Early pulmonary manifestation of cystic fibrosis in children with the DeltaF508/R117H-7T genotype

We report 3 cystic fibrosis newborn screen-positive infants with the DeltaF508/R117H-7T genotype who had Pseudomonas aeruginosa detected in oropharyngeal cultures early in life and a fourth who had pulmonary symptoms and Gram-negative growth on multiple oropharyngeal cultures. All 4 patients were followed prospectively from the time of genetic diagnosis. As many regions implement newborn screening for cystic fibrosis, there is concern regarding which mutations should be included in genetic panels used to make the cystic fibrosis diagnosis. Some have recommended that mutations not specifically associated with classic cystic fibrosis be excluded. Our cases highlight the importance of considering keeping so-called mild mutations on cystic fibrosis newborn screening panels and the need to follow children with these mutations closely

Genetic counseling after implementation of statewide cystic fibrosis newborn screening: Two years\u27 experience in one medical center

PURPOSE: To study the follow-up of genetic counseling performed in families with a newborn detected with one cystic fibrosis (CF) mutation in a statewide newborn screening pilot program. METHODS: Newborns in Massachusetts with an elevated trypsinogen level on newborn screen who are found to have one mutation for CF on a selected mutation assay undergo sweat testing for CF, and their families receive genetic counseling. The genetic counseling focuses on carrier risk for the parents of the newborn and offers carrier testing. We studied the yield of genetic counseling and the resulting genetic testing performed on the families of infants found to be CF carriers who underwent sweat testing in a single institution. RESULTS: Of 102 newborns evaluated with a single CF mutation, 2 (twins) had sweat test results consistent with CF. A total of 101 families were counseled, and 95 were offered DNA-based CF carrier testing. Eighty-two percent of all parents chose to have CF carrier testing, and in five couples, both members were carriers. One of these couples (whose newborn was only a carrier) had an older child who was unexpectedly found to have CF. CONCLUSIONS: Sweat testing of newborns at increased risk for CF in conjunction with genetic counseling for their parents allows identification of infants with CF, finds couples at high risk for having a child with CF, identifies previously undiagnosed siblings with CF, and allows for potential identification of CF carriers in the extended family

Sweat testing infants detected by cystic fibrosis newborn screening

OBJECTIVE: Describe and define limitations of early pilocarpine iontophoresis (sweat testing) for cystic fibrosis (CF) newborn screening (NBS). STUDY DESIGN: Population-based results from follow-up of CF NBS-positive newborns. RESULTS: Insufficient quantity of sweat is more likely if the sweat test is done too early, but testing is generally successful after 2 weeks of age. Sweat chloride levels drop over the first weeks of life. CF carriers have higher sweat chloride concentrations than non-carriers. CONCLUSIONS: Sweat testing can be performed effectively after 2 weeks of age for CF NBS-positive newborns. Earlier testing has a higher risk of insufficient sweat for completing testing

Cystic fibrosis newborn screening: using experience to optimize the screening algorithm

Newborn screening (NBS) for cystic fibrosis (CF) offers the opportunity for early diagnosis and improved outcomes in patients with CF and has been universally available in the state of Massachusetts since 1999 using an immunoreactive trypsinogen (IRT)-DNA algorithm. Ideally, CF NBS is incorporated as part of an integrated NBS system that allows for comprehensive and coordinated education, laboratory screening, clinical follow-up, and evaluation so that evidence-based data can be used to maximize quality improvements and optimize the screening algorithm. The New England Newborn Screening Program (NENSP) retrospectively analyzed Massachusetts\u27s CF newborn screening data that yielded decisions to eliminate a screen-positive category, maintain the IRT cutoff value that prompts the second tier DNA testing, and communicate CF relative risk to primary care providers (PCPs) based on categorization of positive CF NBS results

Communications systems and their models: Massachusetts parent compliance with recommended specialty care after positive cystic fibrosis newborn screening result

OBJECTIVE: To evaluate compliance with recommendations for sweat testing/specialty evaluation and genetic counseling after a positive cystic fibrosis newborn screening (CF NBS) result. STUDY DESIGN: All infants with positive CF NBS results require a diagnostic sweat test at a CF center. Results that were screen positive and diagnosis negative prompted family genetic counseling. Parent compliance with follow-up protocol recommendations was retrospectively analyzed relative to the communications model in place at a particular CF Center. RESULTS: At each of the 5 MA CF centers, 95% of the CF NBS-positive infants completed recommended sweat testing. In contrast, there was wide disparity in compliance (32%-90%) with completion of genetic counseling between CF centers. CONCLUSION: CF centers that escorted parents through the 2 recommended follow-up steps in 1 day had higher compliance with the second step (genetic counseling) than centers that required a return visit for genetic counseling

Lung transplant referral practice patterns: a survey of cystic fibrosis physicians and general pulmonologists

BACKGROUND: Many individuals with cystic fibrosis (CF) die from respiratory failure without referral for lung transplant. Physician practices that may expedite, delay, or preclude referral, are poorly understood. METHODS: Two parallel, web-based surveys focusing on lung transplant referral triggers and barriers, as well as pre-referral evaluation, were emailed to pulmonologists practicing in the New England region. One questionnaire was sent to CF providers (n = 61), and the second to general pulmonary providers practicing at the same institutions (n = 61). RESULTS: There were 43 (70%) responses to the CF provider survey, and 25 (41%) responses to the general pulmonary (‘non-CF’) provider survey. Primary reasons for CF providers to refer their patients included: rapidly declining lung function (91%) and a forced expiratory volume in 1 s (FEV1) below 30% predicted (74%). The greatest barriers to referral for both CF and non-CF providers included active tobacco use (65 and 96%, respectively, would not refer), and active alcohol or other substance use or dependence (63 and 80%). Furthermore, up to 42% of CF providers would potentially delay their referral if triple-combination therapy or other promising new, disease-specific therapy were anticipated. In general, non-CF providers perform a more robust pre-referral medical work-up, while CF providers complete a psychosocial evaluation in higher numbers. Across both groups, communication with lung transplant programs was reported to be inadequate. CONCLUSIONS: Physician-level barriers to timely lung transplant referral exist and need to be addressed. Enhanced communication between lung transplant programs and pulmonary providers may reduce these barriers

Population-based newborn screening for genetic disorders when multiple mutation DNA testing is incorporated: a cystic fibrosis newborn screening model demonstrating increased sensitivity but more carrier detections

OBJECTIVES: Newborn screening for cystic fibrosis (CF) provides a model to investigate the implications of applying multiple-mutation DNA testing in screening for any disorder in a pediatric population-based setting, where detection of affected infants is desired and identification of unaffected carriers is not. Widely applied 2-tiered CF newborn screening strategies first test for elevated immunoreactive trypsinogen (IRT) with subsequent analysis for a single CFTR mutation (DeltaF508), systematically missing CF-affected infants with any of the \u3e1000 less common or population-specific mutations. Comparison of CF newborn screening algorithms that incorporate single- and multiple-mutation testing may offer insights into strategies that maximize the public health value of screening for CF and other genetic disorders. The objective of this study was to evaluate technical feasibility and practical implications of 2-tiered CF newborn screening that uses testing for multiple mutations (multiple-CFTR-mutation testing). METHODS: We implemented statewide CF newborn screening using a 2-tiered algorithm: all specimens were assayed for IRT; those with elevated IRT then had multiple-CFTR-mutation testing. Infants who screened positive by detection of 1 or 2 mutations or extremely elevated IRT (\u3e99.8%; failsafe protocol) were then referred for definitive diagnosis by sweat testing. We compared the number of sweat-test referrals using single- with multiple-CFTR-mutation testing. Initial physician assessments and diagnostic outcomes of these screened-positive infants and any affected infants missed by the screen were analyzed. We evaluated compliance with our screening and follow-up protocols. All Massachusetts delivery units, the Newborn Screening Program, pediatric health care providers who evaluate and refer screened-positive infants, and the 5 Massachusetts CF Centers and their affiliated genetic services participated. A 4-year cohort of 323 506 infants who were born in Massachusetts between February 1, 1999, and February 1, 2003, and screened for CF at approximately 2 days of age was studied. RESULTS: A total of 110 of 112 CF-affected infants screened (negative predictive value: 99.99%) were detected with IRT/multiple-CFTR-mutation screening; 2 false-negative screens did not show elevated IRT. A total of 107 (97%) of the 110 had 1 or 2 mutations detected by the multiple- CFTR-mutation screen, and 3 had positive screens on the basis of the failsafe protocol. In contrast, had we used single-mutation testing, only 96 (87%) of the 110 would have had 1 or 2 mutations detectable by single-mutation screen, 8 would have had positive screens on the basis of the failsafe protocol, and an additional 6 infants would have had false-negative screens. Among 110 CF-affected screened-positive infants, a likely genetic diagnosis was made by the multiple-CFTR-mutation screen in 82 (75%) versus 55 (50%) with DeltaF508 alone. Increased sensitivity from multiple-CFTR-mutation testing yielded 274 (26%) more referrals for sweat testing and carrier identifications than testing with DeltaF508 alone. CONCLUSIONS: Use of multiple-CFTR-mutation testing improved sensitivity and postscreening prediction of CF at the cost of increased referrals and carrier identification