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Melioidosis, an infection caused by the bacterium Burkholderia pseudomallei, is endemic to Southeast Asia and northern Australia but is only very rarely seen in patients in the United States. We report pulmonary B pseudomallei infection in a young girl with cystic fibrosis (CF) who had never traveled to Asia or Australia. Biochemical and epidemiologic investigation determined Aruba as the likely site of disease acquisition. This report highlights the ability of patients with CF to acquire this organism outside of Southeast Asia and describes an aggressive treatment regimen that has kept this patient culture-negative for the organism over a long period of time. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is a genetic disease characterized by dehydration of airway surface liquid and impaired mucociliary clearance. As a result, there is difficulty clearing pathogens from the lung, and patients experience chronic pulmonary infections and inflammation. Clearance of airway secretions has been a primary therapy for those with CF, and a variety of airway clearance therapies (ACTs) have been developed. Because ACTs are intrusive and require considerable time and effort, it is important that appropriate techniques are recommended on the basis of available evidence of efficacy and safety. Therefore, the Cystic Fibrosis Foundation established a committee to examine the clinical evidence for each therapy and provide guidance for their use. A systematic review was commissioned, which identified 7 unique reviews and 13 additional controlled trials that addressed one or more of the comparisons of interest and were deemed eligible for inclusion. Recommendations for use of the ACTs were made, balancing the quality of evidence and the potential harms and benefits. The committee determined that, although there is a paucity of controlled trials that assess the long-term effects of ACTs, the evidence quality overall for their use in CF is fair and the benefit is moderate. The committee recommends airway clearance be performed on a regular basis in all patients. There are no ACTs demonstrated to be superior to others, so the prescription of ACTs should be individualized. Aerobic exercise is recommended as an adjunctive therapy for airway clearance and for its additional benefits to overall health. [ABSTRACT FROM AUTHOR]

RATIONALE: Cystic fibrosis is a recessive genetic disease characterized by dehydration of the airway surface liquid and impaired mucociliary clearance. As a result, individuals with the disease have difficulty clearing pathogens from the lung and experience chronic pulmonary infections and inflammation. Death is usually a result of respiratory failure. Newly introduced therapies and aggressive management of the lung disease have resulted in great improvements in length and quality of life, with the result that the median expected survival age has reached 36 years. However, as the number of treatments expands, the medical regimen becomes increasingly burdensome in time, money, and health resources. Hence, it is important that treatments should be recommended on the basis of available evidence of efficacy and safety. OBJECTIVES: The Cystic Fibrosis Foundation therefore established a committee to examine the clinical evidence for each therapy and to provide guidance for the prescription of these therapies. METHODS: The committee members developed and refined a series of questions related to drug therapies used in the maintenance of pulmonary function. We addressed the questions in one of three ways, based on available evidence: (1) commissioned systematic review, (2) modified systematic review, or (3) summary of existing Cochrane reviews. CONCLUSIONS: It is hoped that the guidelines provided in this article will facilitate the appropriate application of these treatments to improve and extend the lives of all individuals with cystic fibrosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Platelets are an important, albeit generally underappreciated, component of the inflammatory cascade. Platelets are known to contribute to inflammation in atherosclerosis, stroke, and asthma. They produce a large number of proinflammatory lipid mediators and cytokines, and play a vital role in recruitment of leukocytes into inflamed tissue. We review the role of platelets in inflammation, how they assist in the recruitment of leukocytes into lung tissue in asthma, and evidence of their dysfunction in cystic fibrosis (CF). Platelet dysfunction in CF could contribute to pulmonary inflammation and tissue destruction. We hypothesize that platelet activation is important in CF lung disease and suggest research avenues that might help elucidate the role of activated platelets in CF. [ABSTRACT FROM AUTHOR]

Background: Highly effective CFTR modulator therapy (HEMT) has improved the health of many people with cystic fibrosis (pwCF), offering opportunities to discontinue burdensome therapies. SIMPLIFY included randomized, controlled trials that confirmed non-inferiority of discontinuing versus continuing dornase alfa (DA) or hypertonic saline (HS) for 6 weeks in pwCF on HEMT. In this study of post-trial treatment use by SIMPLIFY participants, we hypothesized that randomization to discontinue DA or HS during the trial would be associated with a higher likelihood of non-use of each medication during follow-up., Methods: We electronically surveyed SIMPLIFY participants every 4 weeks for 24 weeks after trial completion but before the main trial results were publicly disclosed. We asked them how often they used medications during the previous week. We estimated covariate-adjusted odds ratios (ORs) of DA or HS non-use by logistic regression with generalized estimating equations., Results: After exclusions mostly due to lack of any surveys, 472 participants were included in the analysis population, 181 from the HS trial and 291 from the DA trial. Approximately half of the analysis population completed all six surveys. At every month of follow-up in both trials, the percentage of individuals reporting non-use of DA or HS during the previous week was greater among those randomized to discontinue therapy. Among participants with responses at 24 weeks, 30/122 (24.6 %) in the HS trial and 79/222 (35.6 %) in the DA trial reported non-use of the respective study medication. After adjusting for covariates, participants randomized to discontinue DA were 8.7-times (95 % CI: 4.3-17.7) more likely to not use DA during follow-up than those randomized to continue DA, and participants randomized to discontinue HS were 5.2-times (95 % CI: 2.1-12.8) more likely to not use HS during follow-up compared to those randomized to continue., Conclusions: In healthy pwCF on ETI, randomization to discontinue DA or HS during SIMPLIFY was associated with greater odds of not using each medication after the trial compared to randomization to continue. These findings suggest that participation in a treatment discontinuation trial can influence participants' post-trial treatment decisions. This possibility may be relevant during discussions about research participation and clinical care., Competing Interests: Declaration of competing interest AHG was supported by a grant from the Cystic Fibrosis Foundation (SIMPLIFY-GIFFOR20K0-CI). KR was supported by a grant from the Cystic Fibrosis Foundation (RIEKER15PE0). NM-H was supported by a grant from the Cystic Fibrosis Foundation (HAMBLE20K0). DPN was supported by a grant from the Cystic Fibrosis Foundation (NICHOL20K0). KO-D, MK, BPO, GJO, SLM, JPC, and GSS have no financial conflict of interest to disclose related to this study., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Reducing treatment burden is a priority for people with cystic fibrosis, whose health has benefited from using new modulators that substantially increase CFTR protein function. The SIMPLIFY study aimed to assess the effects of discontinuing nebulised hypertonic saline or dornase alfa in individuals using the CFTR modulator elexacaftor plus tezacaftor plus ivacaftor (ETI)., Methods: The SIMPLIFY study included two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials at 80 participating clinics across the USA in the Cystic Fibrosis Therapeutics Development Network. We included individuals with cystic fibrosis aged 12-17 years with percent predicted FEV 1 (ppFEV 1 ) of 70% or more, or those aged 18 years or older with ppFEV 1 of 60% or more, if they had been taking ETI and either (or both) mucoactive therapies (≥3% hypertonic saline or dornase alfa) for at least 90 days before screening. Participants on both hypertonic saline and dornase alfa were randomly assigned to one of the two trials, and those on a single therapy were assigned to the applicable trial. All participants were then randomly assigned 1:1 to continue or discontinue therapy for 6 weeks using permuted blocks of varying size, stratified by baseline ppFEV 1 (week 0; ≥90% or <90%), single or concurrent use of hypertonic saline and dornase alfa, previous SIMPLIFY study participation (yes or no), and age (≥18 or <18 years). For participants randomly assigned to continue their therapy during a given trial, this therapy was instructed to be taken at least once daily according to each participant's pre-existing, clinically prescribed regimen. Hypertonic saline concentration was required to be at least 3%. The primary objective for each trial was to determine whether discontinuing was non-inferior to continuing, measured by the 6-week change in ppFEV 1 in the per-protocol population. We established a non-inferiority margin of -3% for the difference between groups in the 6-week change in ppFEV 1 . Safety outcomes were analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT04378153., Findings: From Aug 25, 2020, to May 25, 2022, a total of 672 unique participants were screened for eligibility for one or both trials, resulting in 847 total random assignments across both trials with 594 unique participants. 370 participants were randomly assigned in the hypertonic saline trial and 477 in the dornase alfa trial. Participants across both trials had an average ppFEV 1 of 96·9%. Discontinuing treatment was non-inferior to continuing treatment with respect to the absolute 6-week change in ppFEV 1 in both the hypertonic saline trial (-0·19% [95% CI -0·85 to 0·48] in the discontinuation group [n=133] vs 0·14% [-0·51 to 0·78] in the continuation group [n=140]; between-group difference -0·32% [-1·25 to 0·60]) and dornase alfa trial (0·18% [-0·38 to 0·74] in the discontinuation group [n=199] vs -0·16% [-0·73 to 0·41] in the continuation group [n=193]; between-group difference 0·35% [-0·45 to 1·14]), with consistent results in the intention-to-treat populations. In the hypertonic saline trial, 64 (35%) of 184 in the discontinuation group versus 44 (24%) of 186 participants in the continuation group and, in the dornase alfa trial, 89 (37%) of 240 in the discontinuation group versus 55 (23%) of 237 in the continuation group had at least one adverse event., Interpretation: In individuals with cystic fibrosis on ETI with relatively well preserved pulmonary function, discontinuing daily hypertonic saline or dornase alfa for 6 weeks did not result in clinically meaningful differences in pulmonary function when compared with continuing treatment., Competing Interests: Declaration of interests GR-B reports grants and contracts from Vertex Pharmaceuticals and the Cystic Fibrosis Foundation (CFF). SHD reports contracts from AstraZeneca, Calithera, CFF, US National Institutes of Health (NIH), Vertex Pharmaceuticals; consulting fees from Polarean, 501 Ventures, and Chiesi USA; fees for advisory boards for Enterprise Therapeutics and Gilead Sciences; and participation on a data safety monitoring board (DSMB) for Abbvie and Boehringer Ingleheim. JLT-C reports grants and contracts from CFF, Vertex Pharmaceutics, Eloxx, and 4DMT; consulting fees from Vertex Phamaceuticals, Insmed, and 4DMT; participation on a DSMB for Abbvie; and serving on an advisory board for CFF, American Thoracic Society (ATS), Journal of Cystic Fibrosis, and Emily's Entourage. KAR reports grants from CFF; royalties from Springer Publishing; honoraria from Vertex Pharmaceuticals; and serving on an advisory board for ATS. AB reports grants from the CFF for Therapeutics Development Network (TDN) studies. FR reports grants from Vertex Phamaceuticals and consulting fees from Vertex Phamaceuticals, Proteostasis, Translate Bio, Boehringer Ingelheim, and Calithera. JKY reports grants from CFF. SM reports grants from CFF to support TDN studies. DPN reports grants from CFF and NIH; consulting fees from BiomX, Clarametyx, Genentech, GlaxoSmithKline, Nabriva, Respirion, and Vertex Pharmaceuticals; and advisory board membership for CFF and Kither Biotechnology. DR reports grants and contracts from CFF and Vertex Pharmaceuticals. AHG reports grants and contracts from CFF, Insmed, AbbVie, and 4D Molecular Therapeutics. GSS reports advisory board participation for Vertex Pharmaceuticals and Gilead Sciences. CHG reports grants and contracts from CFF, NIH, and the US Food and Drug Administration; consulting fees from Enterprise Therapeutics; and honoraria from Gilead Sciences, Novartis, Boehringer Ingelheim, Vertex Phamaceuticals, and stock options in Aer Therapeutics. JPC reports employment at the CFF. NM-H reports grants from CFF, NIH, and US Food and Drug Administration; consulting fees from Enterprise Therapeutics; and DSMB membership for the NIH. BPO, KO-D, AHG, GO, CA, RR, and KM declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Obesity and asthma are epidemic in the United States and obesity is an independent risk factor for asthma. Low vitamin D levels (i.e. serum 25-hydroxyvitamin D) have been reported in patients with reduced lung function, more frequent respiratory infections, and asthma exacerbations. Experts have proposed that serum levels > 40 ng/mL are required to offer the immunomodulatory benefits of vitamin D. Low vitamin D levels are common in both obesity and asthma, but it is not known whether supplementation with vitamin D improves asthma symptoms. Guidance for drug development stresses the importance of early phase studies to establish accurate population pharmacokinetics (PK) and drug dosing prior to larger phase 3 trials. The PK of this fat-soluble vitamin in children with increased adiposity are unknown; as are the doses need to reach proposed immunomodulatory levels. The objective of this study is to characterize the PK of vitamin D in children with obesity. Children ages 6--18 years who had physician diagnosed asthma and a body mass index (BMI) >85th percentile will be randomized to receive either standard daily dosing or loading doses followed by standard daily dosing. Blood samples will be obtained to characterize the PK of vitamin D. The results of this study will be used to identify a sufficient dose of vitamin D supplement to raise serum levels above a pre-specified value that may result in anti-inflammatory actions that could improve asthma symptoms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Excess adipose tissue predisposes to an enhanced inflammatory state and can contribute to the pathogenesis and severity of asthma. Vitamin D has anti-inflammatory properties and low-serum levels are seen in children with asthma and in children with obesity. Here we review the intersection of asthma, obesity, and hypovitaminosis D in children. Supplementation with vitamin D has been proposed as a simple, safe, and inexpensive adjunctive therapy in a number of disease states. However, little research has examined the pharmacokinetics of vitamin D and its therapeutic potential in children who suffer from obesity-related asthma., (© 2020 Wiley Periodicals LLC.)

Objective: To describe pancreatic function during the first year of life in infants diagnosed with cystic fibrosis (CF) using serial fecal elastase measurements., Study Design: This was a longitudinal study of 82 infants diagnosed with CF through newborn screening. Monthly stool samples were sent to a central laboratory for fecal elastase measurements., Results: A total of 61 infants had an initial stool sample obtained at age <3.5 months and a final stool sample obtained at age >9 months. Twenty-six of 29 infants with a fecal elastase value <50 μg/g at study entry had a fecal elastase value <200 μg/g (the accepted cutoff value for pancreatic insufficiency) on all measurements during the year; all 29 had a value <200 μg/g at the end of the study. Of the 48 infants with initial fecal elastase value <200 μg/g, 13 had at least 1 fecal elastase value >200 μg/g but had a final stool fecal elastase value <200 μg/g; however, 4 infants with an initial fecal elastase value <200 μg/g ended the year with a value >200 μg/g. Eleven of 13 infants with an initial fecal elastase value of >200 μg/g still had a value >200 μg/g at the end of the first year., Conclusion: Infants with CF exhibit variability in fecal elastase values during the first year. Infants with a fecal elastase level of 50-200 μg/g at diagnosis should be treated with pancreatic enzyme replacement therapy, but fecal elastase should be remeasured at age 1 year to ensure that those with a falsely low value do not continue to receive pancreatic enzyme replacement therapy unnecessarily. Those with a fecal elastase value >200 μg/g initially can become pancreatic insufficient with time., (Copyright © 2013. Published by Mosby, Inc.)

Cystic fibrosis (CF) is a disease which predisposes individuals to recurrent infective exacerbations of suppurative lung disease; however, empyema is a rare complication in these patients. Empyemas secondary to Staphylococcus aureus and Burkholderia cepacia have been described in patients with CF. We report the case of pleural empyema with mixed S. aureus and Pseudomonas aeruginosa infection in a 34-year-old woman with CF, which was managed with ultrasound-guided pigtail catheter insertion, fibrinolysis, and antibiotic therapy. Physicians should be aware of this unusual complication in CF patients, especially those receiving an immunosuppressive therapy.

The pulmonary vasculitides are a heterogeneous group of diseases that often occur as a component of systemic vasculitic diseases. Most frequently, pulmonary vasculitis is observed in vasculitic syndromes that preferentially affect small vessels. Pulmonary involvement may develop because the lung has an extensive vascular and microvascular network. Sensitising antigens can easily reach the lung, and there are large numbers of vasoactive and activated immune cells in the lung. A diagnosis often can be made on the basis of clinical presentation and serologic studies, but biopsy of skin, nose, kidney, or lung may be necessary to ascertain the precise syndrome., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: To use hyperpolarized (HP) (3)He MR imaging to assess functional lung ventilation in subjects with cystic fibrosis (CF) before and after treatment., Materials and Methods: We performed HP (3)He static ventilation MRI scans on three subjects, using a Philips 3.0 Tesla (T) Achieva MRI scanner, before and after 11 days of in-patient treatment with combined intravenous and inhaled therapies for pulmonary exacerbations of CF. We also collected spirometry data. We quantified pulmonary ventilation volume measured with HP (3)He MRI using an advanced semi-automated analysis technique., Results: Following 11 days of treatment with intravenous antibiotics, hypertonic saline, and rhDNase, HP (3)He MR images in one subject displayed a 25% increase in total ventilation volume. Total ventilation volume in the other two subjects slightly decreased. All three subjects showed increases in FEV(1) and FVC following treatment., Conclusion: In all subjects, the HP (3)He MR images provided detailed information on precisely where in the lungs gas was reaching. These data provide additional support for the conclusion that HP noble gas MRI can be a powerful tool for evaluating lung ventilation in patients with cystic fibrosis, but also raise important questions about the correlation between spirometry and HP gas MRI measurements., (Copyright © 2011 Wiley Periodicals, Inc.)

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's 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.

In February 2010, aztreonam for inhalation solution (Cayston; Gilead) - an inhalable formulation of the monobactam antibiotic aztreonam and lysine - was approved by the US FDA to improve respiratory symptoms in patients with cystic fibrosis infected with Pseudomonas aeruginosa.

There is strong evidence that early, aggressive therapy of lung disease leads to improved quality and quantity of life for patients with cystic fibrosis (CF). The treatment of pulmonary disease associated with CF is multifactorial, encompassing prophylaxis, aggressive treatment of infection, use of antiinflammatory agents, and treatment of severe complications. Chest physiotherapy on a regular basis, perhaps using new modalities that allow patient autonomy, is also crucial. This review covers the pathogenesis of CF lung disease and current approaches to therapy, highlighting guidelines recently published by the Cystic Fibrosis Foundation. Clinicians caring for patients with CF should maximize current therapies with the goal of preserving lung function until the time a more definitive curative or controller medication is developed. Empowering patients in the process of providing their own care is a key to achieving this goal., (Copyright Thieme Medical Publishers.)

Cystic fibrosis is the most common lethal genetic disease in white populations. The outlook for patients with the disease has improved steadily over many years, largely as a result of earlier diagnosis, more aggressive therapy, and provision of care in specialised centres. Researchers now have a more complete understanding of the molecular-biological defect that underlies cystic fibrosis, which is leading to new approaches to treatment. One of these treatments, hypertonic saline, is already in use, whereas others are in advanced stages of development. We review clinical care for cystic fibrosis and discuss recent advances in the understanding of its pathogenesis, implementation of screening of neonates, and development of therapies aimed at treating the basic defect.

Objective: The purpose of this preliminary study was to determine normal oropharyngeal flora in healthy, non-CF infants in order to help care givers better interpret culture results obtained from infants with CF., Methods: Oropharyngeal cultures were obtained from 104 healthy infants <12 months old. Cultures were obtained using the same methods as for CF patients and were inoculated onto routine CF culture media. Approximately 20 infants from each of 5 age groups (0-2 days, 3 days to <3 months, 3 months to <6 months, 6 months to <9 months or 9 months to <1 year) were included in the well child sample. In addition, we reviewed serial results of upper airway cultures obtained during the first year of life from 20 CF-affected infants whose diagnosis was suggested by newborn screening., Results: Well infants in the first 48 hr of life had very few pathogenic organisms found in their oropharyngeal cultures; 1/21 had S. aureus. Of the 83 samples from infants over 48 hr of age, we found that 27% (23/83) had S. aureus in their oropharyngeal cultures. Many infants had polymicrobial cultures. Eleven percent of culture samples had E. coli, E. cloacae, H. influenzae, or M. catarrhalis. Three of 83 cultures were positive for non-mucoid Ps. aeruginosa (3.6%), while 2 others were positive for Ps. putida., Conclusion: Healthy infants can have multiple gram-negative and gram-positive organisms recovered from their oropharynx. S. aureus and enteric gram-negative organisms, including non-mucoid Ps. aeruginosa, can be found in the oropharynx of well children up to 1 year of age. Care should be taken to not over interpret the presence of some of these organisms in the oropharyngeal cultures of asymptomatic CF infants., ((c) 2009 Wiley-Liss, Inc.)

Background: An altered distribution of fatty acids in cells and tissues is found in patients with cystic fibrosis (CF). In this study, we assessed the potential role of plasma fatty acid analysis in the diagnosis of CF., Methods: In this 2-part study, we first used gas chromatography-mass spectrometry to analyze fatty acids in plasma from 13 CF patients and 11 controls without CF. We then used the fatty acid distribution data to identify the fatty acids or multiple fatty acid calculations most effective in identifying CF patients. Part 2 of the study was a blinded analysis of 10 CF patients and 9 controls to directly test the effectiveness of the diagnostic parameters for CF identified from the plasma fatty acid analysis., Results: In the nonblinded trial, the multiplication product of (18:2 n-6) x (22:6 n-3) (each as percentage of total plasma fatty acid) was the most effective indicator for distinguishing patients with CF from controls (P = 0.0003). In part 2 (the blinded trial), this multiplication product was also the most effective indicator for distinguishing CF patients from controls (P = 0.0008)., Conclusions: The product of (18:2 n-6) x (22:6 n-3) is effective for distinguishing CF patients from persons without CF. This diagnostic marker may have value as an alternative to the sweat chloride test in selected patients being evaluated for CF.

Introduction: We have previously demonstrated platelet hyperreactivity in cystic fibrosis (CF) patients. Carriers of one CF mutation (heterozygotes) have been shown to have abnormalities related to the presence of only one-half the normal amount of CF transmembrane conductance regulator protein. Platelet hyperreactivity in CF heterozygotes would be an important cardiovascular risk factor, since approximately 1 in 25 Caucasians is a CF carrier., Materials and Methods: We used highly sensitive assays of platelet activation to assess the difference between 16 CF heterozygotes and 16 age- and sex-matched healthy controls without CF mutations., Results: We found no difference in platelet activation between CF heterozygotes and controls., Conclusions: The 50% reduction in the CF transmembrane conductance regulator protein in heterozygotes is insufficient to cause platelet activation.

Objective: To identify necessary components of a successful cystic fibrosis (CF) newborn screening (NBS) program., Study Design: The approach to CF NBS used by the Massachusetts NBS program was examined., Results: Several key components were identified that should be addressed when a state has made the decision to screen, and well in advance of actual implementation. These components include (1) inclusion of CF center directors in the development process; (2) logistics of choosing a screening algorithm relative to practices in place and community wishes; (3) projections of medical service needs from specific algorithms; (4) identification of critical reporting components; (5) identification of critical follow-up components; and (6) recognition of educational needs., Conclusions: Careful examination of a wide variety of issues is needed to ensure optimal implementation of NBS for CF.

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.

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.

Cystic fibrosis (CF) is caused by a mutation of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). We examined platelet function in CF patients because lung inflammation is part of this disease and platelets contribute to inflammation. CF patients had increased circulating leukocyte-platelet aggregates and increased platelet responsiveness to agonists compared with healthy controls. CF plasma caused activation of normal and CF platelets; however, activation was greater in CF platelets. Furthermore, washed CF platelets also showed increased reactivity to agonists. CF platelet hyperreactivity was incompletely inhibited by prostaglandin E(1) (PGE(1)). As demonstrated by Western blotting and reverse-transcriptase-polymerase chain reaction (RT-PCR), there was neither CFTR nor CFTR-specific mRNA in normal platelets. There were abnormalities in the fatty acid composition of membrane fractions of CF platelets. In summary, CF patients have an increase in circulating activated platelets and platelet reactivity, as determined by monocyte-platelet aggregation, neutrophil-platelet aggregation, and platelet surface P-selectin. This increased platelet activation in CF is the result of both a plasma factor(s) and an intrinsic platelet mechanism via cyclic adenosine monophosphate (cAMP)/adenylate cyclase, but not via platelet CFTR. Our findings may account, at least in part, for the beneficial effects of ibuprofen in CF.

Patients with cystic fibrosis (CF) exhibit an excessive host inflammatory response. The aim of this study was to determine (i) whether interleukin 8 (IL-8) secretion is increased from monocytes from subjects heterozygous as well as homozygous for cystic fibrosis transmembrane conductance regulator (CFTR) mutations and (ii) whether this is due to increased cell surface lipopolysaccharide (LPS) receptors or, alternatively, increased activation of mitogen-activated protein kinases (MAPK). The basal level of IL-8 secretion was higher from monocytes from CF patients than from monocytes from healthy controls (P = 0.02) and obligate heterozygotes (parents of the CF patients). The 50% effective concentrations for LPS-induced IL-8 production for monocytes from both CF patients and obligate heterozygotes were 100-fold lower than those for monocytes from healthy controls (P < 0.05). No differences in the levels of IL-1beta production were seen between these groups. Expression of the LPS surface receptors CD14 and Toll-like receptor 4 were not different between CF patients and healthy controls. In contrast, phosphorylation of the MAPKs p38 and ERK occurred at lower doses of LPS in monocytes from patients heterozygous and homozygous for CFTR mutations. These results indicate that a single allelic CFTR mutation is sufficient to augment IL-8 secretion in response to LPS. This is not a result of increased LPS receptor expression but, rather, is associated with alterations in MAPK signaling.

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 >1000 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 (>99.8%; 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.

The aim of this study was to survey cystic fibrosis (CF) patients to determine the frequency of breast-feeding and its association with onset and severity of CF symptoms. Three thousand, two hundred questionnaires were sent to 30 accredited CF centers for anonymous completion. Eight hundred and sixty-three questionnaires were returned and scanned into a database. All results were adjusted for age at time of filling out the questionnaire. Age at onset of symptoms, percent forced expired volume in 1 sec (FEV1%) predicted, and intravenous (IV) antibiotic use were analyzed based on breast-feeding history. Approximately 49% of respondents received human breast milk at some time, but only 18% were exclusively breast-fed. Breast-feeding exclusively for greater than 6 months was associated with a decrease in disease severity based on recent intravenous antibiotic use compared to no breast-feeding (P = 0.03). There was no statistically significant change in onset of symptoms in the setting of breast-feeding; however, a trend toward delayed onset was seen in those receiving human milk. Fifty-three percent of those who breast-fed exclusively > or = 6 months had FEV1% values > 90%, compared to 47% of those not breast-fed. This is a suggestive but not statistically significant difference. In conclusion, breast-feeding for > or = 6 months is associated with decreased use of intravenous antibiotics in the 2 years prior to administering the questionnaire. This survey indicates that breast-feeding is not harmful to children with CF, and may be beneficial., (Copyright 2004 Wiely-Liss, Inc.)

Study Objective: To evaluate the practice of using nasopharyngoscopy without routine fiberoptic bronchoscopy for children presenting to a pediatric pulmonary practice with nonspecific noisy breathing., Design: Retrospective chart review. Records of patients who underwent nasopharyngoscopy between January 1, 1990, and December 31, 1999, were reviewed. Follow-up was obtained by office records and direct contact with the patient's family and/or primary care physician., Setting: Academic, tertiary care facility., Results: Eighty-one children who underwent upper airway endoscopy to evaluate noisy breathing consistent with extrathoracic lesions were identified. One child had two evaluations separated by years for differing complaints, making a total of 82 procedures. Stridor was the chief complaint in three fourths of the children. Half of the children with stridor were found to have laryngomalacia. Long-term follow-up was available for 75 of 81 children, with median follow-up of 6 years (range, 1 to 13 years). No medical problems related to missed airway lesions developed in any infants initially evaluated using nasopharyngoscopy., Conclusions: Nasopharyngoscopy without lower airway endoscopy can be used safely for the initial evaluation of noisy breathing in infants and children provided excellent follow-up is available.

A phase I clinical trial was conducted in which recombinant adenovirus containing the cystic fibrosis trans-membrane regulator (CFTR) (Ad2/CFTR) was administered by bronchoscopic instillation or aerosolization to the lungs of cystic fibrosis (CF) patients. In this paper, we evaluate the efficiency of Ad2/CFTR-mediated transduction of bronchial airway cells. The ability of an Ad2/CFTR vector to transduce airway cells was first evaluated in patients to whom the vector was administered by bronchoscopic instillation. Cells at the administration site were collected 2 days after treatment by bronchoscopic brushing. Ad2-specific CFTR DNA was detected in four of five individuals by PCR, and Ad2-specific CFTR RNA was detected in three of five individuals by RT-PCR. Ad2/CFTR-mediated transduction of airway epithelial cells was then determined in CF individuals receiving this vector by aerosol inhalation. Ad2-specific CFTR DNA was detected in 13 of 13 individuals 2 days after aerosolization, and in 3 of 5 individuals 7 days after aerosolization. Ad2-specific RNA was detected in 4 of 13 individuals on day 2, but was not detected in the 5 individuals tested on day 7. The percentage of airway epithelial cells containing nuclear-localized vector DNA was < or =2.4% as determined by fluorescence in situ hybridization (FISH). However, in some cases, a high percentage of nonepithelial mononuclear cells or squamous metaplastic epithelial cells was infected with the adenoviral vector. In conclusion, aerosol administration is a feasible means to distribute adenoviral vectors throughout the conducting airways, but improvements in adenovirus-mediated transduction of airway epithelial cells are necessary before gene therapy for CF will be effective.

Cystic fibrosis (CF), an autosomal recessive disorder resulting from mutations in the cystic fibrosis trans-membrane conductance regulator (CFTR) gene, is the most common lethal genetic illness in the Caucasian population. Gene transfer to airway epithelium, using adenoviruses containing normal CFTR cDNA, leads to transient production of CFTR mRNA and, in some studies, to correction of the airway epithelial ion transport defect caused by dysfunctional CFTR. Inflammatory responses to the adenoviral vector have been reported, particularly at high viral titers. We evaluated the effects of adenovirus-mediated CFTR gene transfer to airway epithelium in 36 subjects with CF (34 individuals, 2 of whom received two separate doses of vector), 20 by lobar instillation and 16 by aerosol administration. Doses ranged from 8 x 10(6) to 2.5 x 10(10) infective units (IU), in 0.5-log increments. After lobar administration of low doses there were occasional reports of cough, low-grade temperature, and myalgias. At the highest lobar dose (2.5 x 10(9) IU) two of three patients had transient myalgias, fever, and increased sputum production with obvious infiltrates on CT scan. After aerosol administration there were no significant systemic symptoms until the 2.5 x 10(10) IU dose, when both patients experienced myalgias and fever that resolved within 24 hr. There were no infiltrates seen on chest CT scans in any of the patients in the aerosol administration group. There were no consistent changes in pulmonary function tests or any significant rise in serum IgG or neutralizing antibodies in patients from either group. Serum, sputum, and nasal cytokines, measured before and after vector administration, showed no correlation with adenoviral dose. Gene transfer to lung cells was inefficient and expression was transient. Cells infected with the vector included mononuclear inflammatory cells as well as cuboidal and columnar epithelial cells. In summary, we found no consistent immune response, no evidence of viral shedding, and no consistent change in pulmonary function in response to adenovirus-mediated CFTR gene transfer. At higher doses there was a mild, nonspecific inflammatory response, as evidenced by fevers and myalgias. Overall, vector administration was tolerated but transfer of CFTR cDNA was inefficient and transgene expression was transient for the doses and method of administration used here.

Tracheal bronchus is a common anomaly that occurs in approximately 2% of people. Two children with multiple medical problems which led to endotracheal intubation are described. The hospital course for each child was complicated by persistent right upper lobe atelectasis. The presence of a tracheal bronchus was not recognized in either case initially; identification of this anatomic variant allowed appropriate changes in airway management. The potential for tracheal bronchus to cause, or be associated with, localized pulmonary problems is reviewed. The diagnosis of tracheal bronchus should be considered early in the course of intubated patients with right upper lobe complications.

The role of leukotriene B4 (LTB4) in the pathogenesis of acute lung injury was examined in endotoxemic pigs. In a preliminary study, the activity and specificity of an LTB4-receptor antagonist, LY-306669, were evaluated. In vitro, LY-306669 completely blocked the functional upregulation of phagocyte opsonin receptors induced by LTB4 but had a much smaller effect on opsonin receptor upregulation induced by platelet-activating factor. In pigs treatment with LY-306669 prevented leukopenia induced by injection of authentic LTB4 but had no effect on the hematologic or hemodynamic effects of PAF or U-48816, a thromboxane-A2 mimetic. In a second study, pigs received an intravenous priming dose of lipopolysaccharide (LPS) at time (t) = -18 h and were randomized to receive 1) no further treatment (n = 5), 2) LPS (250 micrograms/kg over 1 h beginning at t = 0 h) and LY-306669 (10 mg/kg bolus and 3 mg.kg-1.h-1 infusion beginning at t = -15 min) (n = 7), or 3) LPS and vehicle (n = 6). Treatment with LY-306669 significantly ameliorated LPS-induced hypoxemia, pulmonary edema, and alveolitis. These data suggest that LTB4 is an important mediator of pulmonary dysfunction and transendothelial migration of neutrophils in LPS-induced acute lung injury.

Localized pneumothorax adjacent to a collapsed lobe has been reported in children with bronchial obstruction. We present our findings in seven children with a similar phenomenon occurring in association with diffuse obstructive airway disease. The children, aged from 3 weeks to 17 years, were admitted for diffuse obstructive airway disease and, subsequently, developed lobar collapse with adjacent localized pneumothorax. In five of the seven patients there was a paradoxical shift of the mediastinum toward the side of the pneumothorax. In six cases, the pneumothorax resolved spontaneously with lobar reexpansion. A conservative treatment approach to patients with this constellation of radiographic findings appears justified.

We sought to determine whether a standardized "priming" event, namely a small dose of LPS, would alter physiological responses to a subsequent larger "challenge" dose of endotoxin. Accordingly, four groups of pigs (N = 5-6) were studied. One group received neither priming nor challenge doses of LPS. A second group were not primed but were infused with a challenge dose (250 micrograms/kg) of LPS. A third group were pretreated 18 h before being studied with a priming dose of LPS (20 micrograms/kg), but were not infused with a second dose of LPS. A fourth group received both priming and challenge doses of LPS. Priming with LPS exacerbated endotoxin-induced arterial hypoxemia, and decreased animal-to-animal variability in the degree of hypoxemia induced by a challenge dose of endotoxin. Priming blunted the early phase (30 min) and exacerbated the delayed phase (120-210 min) of LPS-induced pulmonary hypertension. Priming blunted LPS-induced release of prostacyclin and thromboxane A2. The use of a priming dose of LPS increases the severity and reproducibility of LPS-induced acute lung injury in swine.

We report our experience giving aerosolized pentamidine as prophylaxis for Pneumocystis carinii pneumonia (PCP) to 9 children (mean age, 7.33 years; range 3-17 years) with leukemia who were unable to tolerate trimethoprim-sulfamethoxazole (TMP-SMX) due to allergy or myelosuppression. The dose of pentamidine was modified for each child to correct for weight and approximate alveolar ventilation. We were able to administer the drug to younger children by using a cushioned face mask in place of the standard mouthpiece. One child experienced moderate coughing with administration of pentamidine. He and four others with a past medical history suggestive of reactive airways disease were pretreated with inhaled albuterol. No other adverse effects were noted. Treatment lasted an average of 8.11 +/- 4.1 months per child; no case of PCP occurred. We conclude that aerosolized pentamidine can be administered to even very young children and may be of benefit to all immunosuppressed children unable to use TMP-SMX prophylaxis. The adjusted dose used here appears to be safe, but further studies regarding drug delivery and efficacy are needed.