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Scoliosis deformity has been linked with deleterious changes in the thoracic cavity that affect pulmonary function. The causal relationship between spinal deformity and pulmonary function has yet to be fully defined. It has been hypothesized that deformity correction improves pulmonary function by restoring both respiratory muscle efficiency and increasing the space available to the lungs. This research aims to correlate pulmonary function and thoracic volume before and after scoliosis correction. Retrospective correlational analysis between thoracic volume modeling from plain x-rays and pulmonary function tests was conducted. Adolescent idiopathic scoliosis patients enrolled in a multicenter database were sorted by pre-operative Total Lung Capacities (TLC) % predicted values from their Pulmonary Function Tests (PFT). Ten patients with the best and ten patients with the worst TLC values were included. Modeled thoracic volume and TLC values were compared before and 2 years after surgery. Scoliosis correction resulted in an increase in the thoracic volume for patients with the worst initial TLCs (11.7%) and those with the best initial TLCs (12.5%). The adolescents with the most severe pulmonary restriction prior to surgery strongly correlated with post-operative change in total lung capacity and thoracic volume (r2 = 0.839; p

BACKGROUND: Objective measures of adherence to high-frequency chest wall compression (HFCWC), a form of airway clearance therapy for patients with cystic fibrosis, are lacking. We used a novel electronic monitoring device integrated into an HFCWC vest to measure adherence compared with self-reported adherence. We determined factors that influenced adherence and how adherence correlated with baseline pulmonary function and pulmonary exacerbations. METHODS: Data were collected by direct measurement of date, time of day, and duration of HFCWC use to determine the number of daily treatments and daily duration of treatments. Chart review provided prescribed airway clearance therapy treatment and demographic and clinical information. Subject and caregiver report of the daily number of airway clearance therapy treatments was obtained by telephone interviews. Analysis used 2-sample and paired t test, analysis of variance, and linear regression. RESULTS: Average adherence was 69%. Adherence was highest in children (82%, P = .02) and those receiving assistance with treatment (82%, P < .001). Subjects overestimated therapy duration from a mean ± SD of 127 ± 169% by adults to 19.2 ± 26.3% by parents or guardians of children. Average adherence decreased with increasing prescribed therapy time (P = .02). Average daily therapy time and adherence had significant positive associations with baseline FEV(1) percent of predicted (P = .02 and P = .02, respectively) and negative associations with pulmonary exacerbations during the pre-study period and at baseline (P = .044 and P = .02, respectively). CONCLUSIONS: Greater adherence to HFCWC measured directly by a novel recorder was associated with better baseline pulmonary function and fewer exacerbations in the pre-study and baseline period. Adherence decreased with age and prescribed therapy time and increased with therapy assistance. Self-report overestimation is large and thus not an accurate measure of adherence.

Summary Background Antibiotic treatment of cystic fibrosis pulmonary exacerbations is inconsistent. Previous research has indicated that intravenous antibiotics are used more frequently at sites with better pulmonary function but it is not clear under what circumstances they are prescribed. Method Pediatric care sites enrolled in the Epidemiologic Study of Cystic Fibrosis were ranked by median FEV1 % predicted of children they followed. Reported presence of new signs and symptoms of a pulmonary exacerbation (PEx) and antibiotic treatment within 21 days were compared between those in the highest vs. those in the other quartiles, and adjusted for sociodemographic and clinical characteristics of patients. Result Highest quartile sites had a total of 2,454 children eligible for this analysis; lower quartile sites had a total of 5,487. The odds of having a PEx at highest vs. lower sites varied with how the PEx was defined, but high quartile sites were uniformly more likely to treat PEx with antibiotics. The adjusted odds ratio for treatment with any antibiotics of a PEx defined by the occurrence of one or two new signs and symptoms was 1.24 (95% CI 1.10, 1.40); for treatment of a PEx defined by the occurrence of three or four new signs and symptoms was 1.50 (95% CI 1.06, 2.11); and for treatment of a PEx defined by a drop of FEV1 by ≥–15% was 1.33 (1.10, 1.60). The adjusted OR for treatment of these PEx with IV antibiotics was 1.11 (0.94, 1.32), 1.90 (1.32, 2.72), and 1.33 (1.10, 1.60), respectively. Conclusion ESCF care sites in the highest quartile for FEV1 were more likely to prescribe antibiotics when patients present with either mild or overt evidence of PEx. While this may not be the only reason that their patients have superior median FEV1, it is likely an important contributor. Pediatr Pulmonol. 2015; 50:431–440. © 2014 Wiley Periodicals, Inc.

Rationale: Recent literature suggests vitamin D has an effect on lung function and on the lung’s ability to fight infection, both important in the cystic fibrosis (CF) population as predictors of morbidity and mortality. Objectives: Our study assessed associations between vitamin D and % predicted lung function, pulmonary exacerbations, and first Pseudomonas aeruginosa infection in children with CF. We hypothesized that children with CF who have 25-hydroxy vitamin D (25-OHD) levels less than 30 μg/L would have lower % predicted lung function and more pulmonary exacerbations than those with 25-OHD greater than or equal to 30 μg/L. Methods: This retrospective longitudinal study of 130 children aged 6 to 18 years between 2000 and 2012 examined 25-OHD levels classed in three vitamin D groups: sufficient (≥30 μg/L), insufficient (20–29 μg/L), and deficient (

Cystic fibrosis related diabetes (CFRD) is characterized by progressive insulin insufficiency. It is extraordinarily prevalent in the cystic fibrosis (CF) population, occurring in 15–20% of adolescents and, eventually, more than half of adults (1). Few of the remaining patients have completely normal glucose metabolism; even those with normal fasting and 2-hour oral glucose tolerance test (OGTT) glucose levels typically have mid-OGTT glucose elevation and have defective acute insulin secretion in response to intravenous glucose (2). While CFRD does not usually develop before puberty, it has its roots in childhood and glucose intolerance is common in 6–9 year old children with CF (3). It has not been studied in younger children, but ferret models of CF demonstrate insulin secretory abnormalities in the newborn period (4), suggesting that there may be an intrinsic defect in beta-cell function in CF. CF is caused by abnormalities in the CF transmembrane conductance regulator (CFTR), an ATP-binding cassette transporter-class ion channel involved in chloride, sodium and water transport and absorption across cell membranes. CFTR defects lead to thick, viscous secretions with well-known chronic complications including obstructive lung disease associated with infection and inflammation, sinusitis, intestinal obstruction, liver disease and infertility. Pancreatic exocrine insufficiency develops as plugged ductules prevent digestive enzymes from reaching the gut; autodigestion of the pancreas by these trapped enzymes leads to fibrosis. It has long been debated whether insulin insufficiency in CF is merely a physical, “by-stander” consequence of this fibrotic destruction of the pancreatic architecture, or if CFTR defects per se impact insulin secretion (5). CFTR is expressed in human and mouse pancreatic alpha- and beta-cells (6; 7), but it is not known whether it is involved in hormone secretion. There has previously been no way to directly test this in a human model. Ivacaftor (VX-770, Kalydeco™, Vertex Pharmaceuticals, Cambridge, MA) is the first of a group of “potentiator” molecules being developed to correct the CFTR defect. CFTR is made in the endoplasmic reticulum, processed in the Golgi apparatus, and secreted in vesicles which chaperone proteins carry to the cell membrane, where it must be inserted and then must function normally. Defects leading to CF may occur at any of these steps. In patients with the G551D mutation (about 4% of the CF population), CFTR is found in the cell membrane but is dysfunctional. Ivacaftor corrects this defect by restoring channel gating, through an as-yet unidentified mechanism (8). In clinical Phase 2 and 3 trials, ivacaftor produced dramatic improvements in skin sweat chloride levels and in lung function within just 3 weeks (9; 10), and the drug has recently been approved by the FDA in children down to age 6. The initiation of ivacaftor therapy offers a unique opportunity to test the role of CFTR in human insulin secretion, potentially opening the way for novel diabetes therapies and for prevention or at least amelioration of diabetes in CF.

Background A standard definition of pulmonary exacerbation based on signs and symptoms would be useful for categorizing cystic fibrosis (CF) patients and as an outcome measure of therapy. The frequently used definition of treatment with intravenous antibiotics varies with practice patterns. One approach to this problem is to use large data sets which include a patient’s signs and symptoms along with their clinician’s decision to treat with antibiotics for the diagnosis of pulmonary exacerbation. Previous analysis of such a data set, the Epidemiologic Study of Cystic Fibrosis (ESCF), found that new crackles, increased cough, increased sputum, and weight decline were the four clinical characteristics most strongly influencing providers to treat young CF patients for a pulmonary exacerbation. The objectives of this study were to confirm that these four characteristics influence the decision to treat with antibiotics for a pulmonary exacerbation in young CF patients; to evaluate their implications for future nutritional status and lung function; and to assess the effect of antibiotic treatment on these characteristic signs and symptoms.

Patients with cystic fibrosis (CF) experience frequent pulmonary exacerbations (PExs). Clinicians manage these episodes of worsening signs and symptoms in a variety of ways.To characterize the antibiotic management and associated change in lung function following PExs.We used 2003-2005 data from the Epidemiologic Study of Cystic Fibrosis to examine antibiotic treatment and the immediate and long-term lung function change associated with clinician reported PExs.A total of 45,374 PExs were reported in 13,194 unique patients. Most PExs (73%) were treated with oral antibiotics, while 39% were treated IV and 24% were treated with inhaled antibiotics. The likelihood of non-IV versus IV antibiotic treatment was associated with the patient's age, stage of lung disease, and magnitude of lung function drop prior to the PEx. Following treatment, the average improvement in the FEV1 was 3.4 ± 12.2% predicted with a greater (5.1 ± 12.7% predicted) improvement following IV antibiotic treatment than with non-IV treatment (2.0 ± 11.6% predicted). When the best FEV1 from the year before was compared with 180 days following the PEx there was an average fall of 3.8 ± 10.5% predicted with little difference observed between antibiotic treatment routes. Patients with only one exacerbation during the 3-year study had a similar loss of lung function to patients with no reported exacerbations.Clinicians treat the majority of PExs with oral antibiotics, particularly in younger, healthier patients. Pulmonary function improves with antibiotic therapy, however, PExs are associated with lung function deterioration over time.

Objectives Rapid and reliable confirmatory sweat testing following a positive newborn screen (NBS) for cystic fibrosis (CF) is preferred to allow for early diagnosis and to decrease parental anxiety. The Cystic Fibrosis Foundation (CFF) recently recommended a quantity not sufficient (QNS) rate of ≤ 10% in infants < 3 months of age referred for quantitative sweat chloride analysis. Two CFF-approved methods are available by which to quantitatively measure chloride concentration in sweat. Our objective was to compare the performance of the Macroduct® sweat collection system (MSCS) with the Gibson and Cooke technique (GCT) in the acquisition of samples for the determination of sweat chloride concentration in infants with a positive Minnesota State NBS for cystic fibrosis.

OBJECTIVES The aim of the study was to assess the efficacy of gastrostomy tube (GT) placement on improving nutritional status and pulmonary function in patients with cystic fibrosis (CF). PATIENTS AND METHODS Data were collected from the Minnesota Cystic Fibrosis Database. Subjects with at least 5 percent-predicted forced expiratory volume in 1 second (ppFEV1) and 1 BMI percentile (pBMI) measurements before and after GT placement were included. Median pBMI values were compared 2 years before and 1, 2, and 4 years after GT placement using a signed rank test. Longitudinal mixed model analysis was used to assess the effect of GT placement on ppFEV1. To assess the effect of ppFEV1 at GT placement on efficacy, the estimated ppFEV1 change was regressed against the ppFEV1 level at placement. RESULTS Forty-six subjects with CF who met entry criteria were identified. Mean estimated step changes in ppFEV1 at placement for men, women, boys, and girls were 2.16% (P = 0.52), 0.43% (P = 0.92), 0.99% (P = 0.65), and -0.91% (P = 0.74), respectively. Mean estimated slope changes of ppFEV1 after GT placement were 5.01% (P = 0.02), 4.48% (P = 0.07), 1.49% (P = 0.23), and 4.02% (P = 0.01) per year for men, women, boys, and girls, respectively. Median change in pBMI in the second year after GT placement was 13.3% (P ≤ 0.0001). Estimated coefficients for the effect of ppFEV1 level at placement on the ppFEV1 step and slope change were -0.041 (P = 0.28) and -0.005 (P = 0.84), respectively. CONCLUSIONS GT placement in patients with CF results in significant improvement in both pBMI and ppFEV1, except in women. The change in lung function after GT placement is not dependent on the level of lung function at placement.

Cystic fibrosis (CF) lung disease is characterized by structural changes in the airways and parenchyma. No sputum biomarker exists to measure the degree of active structural destruction during pulmonary exacerbation in patients with CF. The noninvasive measurement of desmosine, a breakdown product of elastin, may reflect ongoing lung injury and serve as a biomarker of short-term damage. Our objectives were to measure desmosine in the sputum of patients with CF hospitalized for treatment of a pulmonary exacerbation and to explore the correlation between desmosine levels and other markers of clinical improvement, including lung function and inflammatory mediators, following hospitalization.Sputum and blood samples collected and lung function measurements were made at multiple time points during hospitalization. We used a repeated measures model, adjusted for age and time between measurements, to compare log-transformed sputum desmosine levels across multiple time points and to correlate those levels with related variables.Desmosine levels were measured by radioimmunoassay in 71 expectorated sputum samples from 19 patients with CF hospitalized for 26 pulmonary exacerbations (range of results, 0 to 200 pmol/L desmosine/mL). Sputum desmosine levels decreased significantly during the first week of hospitalization (p = 0.04). Desmosine levels were positively associated with plasma C-reactive protein (rho = 0.59; p = 0.03), sputum interleukin-8 (rho = 0.86; p0.01), and sputum neutrophil elastase (rho = 0.78; p0.01).Sputum desmosine, a novel measure of acute structural lung injury, may serve as a marker of structural lung damage occurring during exacerbations of lung disease in CF.

The incidence of methicillin resistant Staphylococcus aureus (MRSA) infection is increasing in cystic fibrosis (CF), but the impact of MRSA detection on clinical outcomes is unclear. Our objective was to determine whether incident detection of MRSA is associated with a change in pulmonary function over time in CF patients. We analyzed data from the Epidemiologic Study of Cystic Fibrosis (ESCF), a prospective observational study of CF patients in North America. Multivariable piecewise linear regression was used to model the impact of incident detection of MRSA on pulmonary function over time, measured by percent predicted forced expiratory volume in one second (FEV1% predicted), adjusting for potential confounders. There were 5,090 patients ≥6 years old who were MRSA negative for at least 2 calendar years. Five hundred ninety-three (12%) of these patients acquired MRSA during the years 2001–2003, with detection rates of MRSA during those years rising from 4.4% to 6.9%. MRSA positive patients had a lower FEV1% predicted and received more antibiotic and other therapies than patients who remained MRSA negative. After adjusting for antibiotic therapy and other potential confounders, MRSA positive patients also had a higher rate of decline in FEV1% predicted both before and after the incident culture, although the rate of FEV1% predicted decline did not change significantly after MRSA detection. In conclusion, although MRSA in CF was a marker for more aggressive therapy and may reflect increased disease severity, incident MRSA detection was not associated with a changing rate of FEV1% predicted decline. Pediatr. Pulmonol. 2008; 43:1117–1123. © 2008 Wiley-Liss, Inc.

Ivacaftor has been shown to be a safe, effective treatment for cystic fibrosis in patients aged 6 years or older with a CFTR gating mutation. We aimed to assess the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in children aged 2-5 years.In the two-part KIWI study, we enrolled children aged 2-5 years weighing 8 kg or more with a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the USA, UK, and Canada. Participants received oral ivacaftor 50 mg (if bodyweight14 kg) or 75 mg (if bodyweight ≥14 kg) every 12 h for 4 days in part A (to establish the short-term safety of doses for subsequent assessment in part B), and then for 24 weeks in part B (to assess safety and longer-term pharmacodynamics). Children could participate in both or just one part of the study. Primary outcomes were pharmacokinetics and safety, analysed in all patients who received at least one dose of ivacaftor. Secondary outcomes were absolute change from baseline in sweat chloride concentrations and bodyweight, body-mass index (BMI), and height Z scores, and pharmacokinetic parameter estimation of ivacaftor. This study is registered with ClinicalTrials.gov, number NCT01705145.Between Jan 8, 2013, and March 1, 2013, nine patients were enrolled onto part A of the study, all of whom completed the 4 day treatment period, and eight of whom took part in part B. Between June 28, 2013, and Sept 26, 2013, 34 patients were enrolled in part B, 33 of whom completed the 24 week treatment period. All patients received at least one dose of ivacaftor. Results of ivacaftor pharmacokinetics suggested that exposure was similar to that reported in adults (median Cmin were 536 ng/mL for the 50 mg dose; 580 ng/mL for the 75 mg dose; median ivacaftor AUC values were 9840 ng × h/mL and 10 200 ng × h/mL, respectively). Common adverse events in part B included cough (in 19 [56%] of 34 patients) and vomiting (in ten [29%]). Five (15%) patients had liver function test (LFT) results that were more than eight times higher than the upper limit of normal, four of whom had study drug interrupted, and one of whom had study drug discontinued. Six (18%) of 34 patients had seven serious adverse events; a raised concentration of transaminases was the only serious adverse event regarded as related to ivacaftor and the only adverse event that resulted in study treatment discontinuation. At week 24, in patients for whom we had data, sweat chloride had changed from baseline by a mean of -46·9 mmol/L (SD 26·2, p0·0001), weight Z score by 0·2 (0·3; p0·0001), BMI Z score by 0·4 (0·4, p0·0001), and height Z score by -0·01 (0·3; p=0·84).Ivacaftor at doses of 50 mg and 75 mg seems to be safe in children aged 2-5 years with cystic fibrosis with a gating mutation followed up for 24 weeks, although the frequency of elevated LFTs suggests that monitoring should be frequent in young children, particularly those with a history of elevated LFTs. Results of an ongoing extension study assessing durability of these effects and longer-term safety are warranted.Vertex Pharmaceuticals Incorporated.

Patients with inherited metabolic storage disorders are at a higher risk of developing pulmonary complications after hematopoietic cell transplantation (HCT). This single-center prospective study of 48 consecutive inherited metabolic storage disorder patients was performed to identify risk factors for the development of pulmonary complications after HCT. Before HCT, subjects underwent bronchoalveolar lavage (BAL) for cell count, culture, nitrite levels, and analysis of proinflammatory cytokines and chemokines. The overall incidence of pulmonary complications was 52% (infectious, 23%; noninfectious, 29%) over a period of 4 years. Diffuse alveolar hemorrhage was the most frequent noninfectious complication and occurred in 19% of patients, all of whom had a diagnosis of mucopolysaccharidosis (Hurler and Maroteaux-Lamy syndromes). Levels of interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor alpha, macrophage inflammatory protein 1alpha, and granulocyte colony-stimulating factor in BAL fluid samples obtained before HCT were higher in patients with mucopolysaccharidoses than in patients with leukodystrophies. In addition, levels of IL-1beta, IL-6, IL-8, and granulocyte colony-stimulating factor were increased in the BAL fluid of patients who developed noninfectious pulmonary complications compared with those who did not develop pulmonary complications. It is interesting to note that most noninfectious pulmonary complications occurred in patients with mucopolysaccharidoses, especially diffuse alveolar hemorrhage, which occurred exclusively in patients with mucopolysaccharidoses. Higher levels of bronchial proinflammatory cytokines and chemokines may be predictive of the development of subsequent posttransplantation noninfectious complications in patients with mucopolysaccharidoses, especially those with Hurler syndrome. Larger studies will be required to further elucidate etiologic mechanisms and predictive factors.

Butyrfentanyl is a potent short-acting opioid and a fentanyl analog with uncertain clinical effects. A review of the literature reveals no human case reports of butyrfentanyl overdose. As the use of analog and synthetic drugs continues to increase, clinicians are often faced with tremendous uncertainty when they encounter patients exposed to these synthetic drugs. We describe, to our knowledge, the first case of a butyrfentanyl overdose that resulted in clinically significant hemoptysis, acute lung injury, hypoxic respiratory failure, and diffuse alveolar hemorrhage. Complicating this case was a false-positive urine drug screen for fentanyl. Clinicians who encounter fentanyl exposures should be aware they may in fact be dealing with butyrfentanyl. As little is known of butyrfentanyl and our patient suffered a significant pulmonary hemorrhage, those who encounter butyrfentanyl exposures should monitor for hemorrhagic complications.

CPX (8-cyclopentyl-1,3-dipropylxanthine) is a novel compound currently under development as a potential treatment for cystic fibrosis (CF). The drug has been shown to increase chloride efflux and CFTR trafficking in vitro in CF airway cells. This phase I multicenter, single-dose, placebo-controlled trial was performed at four institutions. Thirty-seven subjects homozygous for the Delta F(508) allele were studied in an escalating dose protocol of seven single-dose cohorts (1, 3, 10, 30, 100, 300, and 1,000 mg) to evaluate the safety, pharmacokinetics, and efficacy of CPX. Efficacy was determined using nasal transepithelial potential difference and sweat chloride measurements prior to dosing and at 1, 2, and 4 hr postdose. The incidence of adverse events in the treatment group was similar to that with placebo, indicating safety of the single doses studied. One serious adverse event (an acute pulmonary exacerbation) occurred 13 days after dosing, and was not considered related to the study drug. The maximal plasma CPX concentration and total amount of CPX absorbed appeared to be linearly related to dose, but was highly variable throughout the dose range studied, suggesting inconsistent absorption. There was no apparent effect of single-dose administration on either nasal transepithelial potential difference or sweat chloride measurements. The positive safety and pharmacokinetic findings of this study support continued development of CPX as a potential therapeutic for CF.

Cystic fibrosis (CF) is a complex illness characterized by chronic lung infection leading to deterioration in function and respiratory failure in over 85% of patients. An understanding of the risk factors for that progression and the interaction of these factors with current therapeutic strategies should materially improve the prevention of this progressive lung disease. The Epidemiologic Study of Cystic Fibrosis (ESCF) was therefore designed as a multicenter, longitudinal, observational study to prospectively collect detailed clinical, therapeutic, microbiologic, and lung function data from a large number of CF treatment sites in the U.S. and Canada. The ESCF also serves an important role as a phase-IV study of dornase alfa. To be eligible for enrollment, subjects must have the diagnosis of CF and receive the majority of their care at an ESCF site. In this paper, the authors present the ESCF study design in detail. Further, enrollment data collected at 194 study sites in 18,411 subjects enrolled from December 1, 1993 to December 31, 1995 are presented in summary form. This comprehensive study is unique in the detail of clinical data collected regarding patient monitoring and therapeutic practices in CF care. Two companion articles present data regarding practice patterns in cystic fibrosis care, including data on resource utilization and prescribing practices.

Investigators participating in the Epidemiologic Study of Cystic Fibrosis project began to collect microbiological, pulmonary, and nutritional data on cystic fibrosis (CF) patients at 180 North American sites in 1994. Part of this study was a survey undertaken in August 1995 to determine microbiology laboratory practices with regard to pulmonary specimens from CF patients. The survey included a section on test ordering, completed by a site clinician, and a section on test performance and reporting, completed by each site’s clinical microbiology laboratory staff. Seventy-nine percent of the surveys were returned. There was intersite consistency of microbiology laboratory practices in most cases. The majority of sites follow most of the CF Foundation consensus conference recommendations. There were differences in the frequency at which specimens for culture were obtained, in the use of selective media for Staphylococcus aureus and Haemophilus influenzae , and in the use of a prolonged incubation for Burkholderia cepacia . These variations in practice contribute to prevalence differences among sites and may result in differences in clinical care.

Antibiotic treatment of cystic fibrosis pulmonary exacerbations is inconsistent. Previous research has indicated that intravenous antibiotics are used more frequently at sites with better pulmonary function but it is not clear under what circumstances they are prescribed.Pediatric care sites enrolled in the Epidemiologic Study of Cystic Fibrosis were ranked by median FEV1 % predicted of children they followed. Reported presence of new signs and symptoms of a pulmonary exacerbation (PEx) and antibiotic treatment within 21 days were compared between those in the highest vs. those in the other quartiles, and adjusted for sociodemographic and clinical characteristics of patients.Highest quartile sites had a total of 2,454 children eligible for this analysis; lower quartile sites had a total of 5,487. The odds of having a PEx at highest vs. lower sites varied with how the PEx was defined, but high quartile sites were uniformly more likely to treat PEx with antibiotics. The adjusted odds ratio for treatment with any antibiotics of a PEx defined by the occurrence of one or two new signs and symptoms was 1.24 (95% CI 1.10, 1.40); for treatment of a PEx defined by the occurrence of three or four new signs and symptoms was 1.50 (95% CI 1.06, 2.11); and for treatment of a PEx defined by a drop of FEV(1) by ≥-15% was 1.33 (1.10, 1.60). The adjusted OR for treatment of these PEx with IV antibiotics was 1.11 (0.94, 1.32), 1.90 (1.32, 2.72), and 1.33 (1.10, 1.60), respectively.ESCF care sites in the highest quartile for FEV(1) were more likely to prescribe antibiotics when patients present with either mild or overt evidence of PEx. While this may not be the only reason that their patients have superior median FEV(1), it is likely an important contributor.

In cystic fibrosis the bronchiectatic conducting airways have large numbers of neutrophils in their walls and in their luminal contents. The neutrophil's primary granule enzyme activities of elastase and peroxidase are increased in the sputum of these patients. It has been postulated that these enzymes--together or individually--act to damage the airway epithelium. However, only peroxidase activity has consistently correlated with the degree of structural and functional airway disease in these patients with leakage of plasma protein into the airway lumen (Regelmann et al., Pediatr Pulmonol, 1995; 19:1-9). The present study was designed to test whether human neutrophil-derived myeloperoxidase can independently produce bronchial epithelial damage without the presence of proteases, as measured by increased permeability of the airway epithelium. Human peripheral blood neutrophils were purified, their primary granules isolated, and their peroxidase purified using affinity and ion exchange column chromatography. Activity of the proteinase-free peroxidase was measured using a chromogenic substrate. The effect of this peroxidase on the permeability of excised rat tracheas was measured using radioactive and fluorescent-labeled non-ionic molecules of varying molecular weight. Rat tracheas exposed to 15 minute treatments with either 130 U of peroxidase or hydrogen peroxide (10(-5) M) did not show a significant increase in the permeability of the epithelium to [3H]inulin, [14C]sucrose, and fluorescein isothiocyanate dextran 20 compared with control tracheas. However, those tracheas exposed to 130 U peroxidase followed by 10(-5) M hydrogen peroxide showed an increased permeability to each of the three test solutes. We conclude that proteinase-free myeloperoxidase, in the presence of non-toxic concentrations of its substrates, hydrogen peroxide and halide, produced increases in permeability to non-ionic molecules in the rat trachea within 15 minutes.

Because of conflicting data about hospital-based transmission of Burkholderia (Pseudomonas) cepacia, an important respiratory pathogen in cystic fibrosis (CF), we compared strains found in sputum, lung, or blood of 29 CFpatients in our center from 1988 to 1994, studying the relationship between strain and hospital exposure of incident and that of prevalent cases. Exposure was defined as a concurrent hospital stay between a prevalent and an incident case. B. cepacia strains were determined by polymer­ ase chain reaction (PCR) ribotyping and endonuclease subtyping. The 165 to 235 spacer regions of the bacterial ribosomal RNA (rRNA) genes were amplified by PCR, and the product-size patterns used to type each B. cepacia isolate. Endonuclease digestion of the PCR products provided length polymor­ ph isms for subtyping. There were 17 incident events during the period from 1988 to 1994, 16 of which involved a single ribotype. These 16 ribotypes could be divided into five subtypes by endonuclease mapping. Four patients grew B. cepacia from the blood, with the organism being the same strain as found in the lung in each case. Case controls were obtained to evaluate risk factors for B. cepacia acqui­ sition. Concurrent hospitalization with a prevalent case significantly increased the risk of acquisition. There was no association between length of hospitalization, length of exposure, or FEV1 and the risk of B. cepacia acquisition. Shreve MR,Johnson SJ, Milia CE,Wlellnskl Cl., Regelmann WE. PCRrlbotyp­ ing and endonuclease subtyplng in the epidemiology of Burkholderla cepacla Infection. AM J RESPIR CRIT CARE MED 1997;155:984-989. Because Burkholderiacepacia is associated with respiratory de­ cline and sepsis in cystic fibrosis (CF) patients, understanding its pattern of transmission, persistence in the lung, and ability to invade the bloodstream are important. In order to elicit this information, an accurate method of strain typing of the organ­ ism must be available. The exact pattern of B. cepacia transmission is unknown, al­ though person-to-person spread via social contact (1, 2) and hospital-based spread (3, 4) have both been suggested. Transat­ lantic spread of a highly transmissible strain, probably acquired at a CF camp, has also recently been suggested (5). Another study (6) revealed distinct strains in each of a number of hospitalized patients, indicating no evidence for person-to-person spread of B. cepacia. This study also found persistence of strains in in­ dividual patients over time. In the present study, we attempted to ascertain whether there are identifiable risk factors leading to acquisition of B. cepacia. Additionally, B. cepacia can become blood borne in some cases. It has been unclear whether the blood­ borne strains differ from those found in the lung of the same patient.

would not be large; only 20%–30% of cases of AOM in the United States are associated with middle ear specimens that grow S. pneumoniae on culture [2]. Approximately 70% of children with S. pneumoniae–related AOM had S. pneumoniae serotypes contained in or closely related to serotypes contained in PCV7 [3]. At best, then, we expected an overall risk reduction of ∼20% for AOM among US children who completed the PCV7 vaccination course. Among 37,868 infants randomly assigned to receive either PCV7 or meningococcus type C conjugate vaccine in California, those receiving PCV7 experienced a 7.8% relative risk reduction in clinically diagnosed cases of AOM (95% CI, 5.2%–10.5%), and a 20% relative risk reduction in the placement of ventilatory tubes (95% CI, 3.6%–34.1%) [4]. Investigators in Finland found a 6% relative risk reduction in AOM among 831 infants receiving PCV7, compared with 831 receiving hepatitis B vaccine [5]. The 95% CI for the protective efficacy of the vaccine against AOM in this study was 4% to 16%. This has been interpreted as an indication that vaccine use might actually increase the frequency of AOM. This has some biological plausibility, because the increase in the incidence of AOM attributable to S. pneumoniae serotypes or to other otopathogens not contained in the vaccine might be greater than the decrease in the incidence of AOM attributable to S. pneumoniae serotypes contained in PCV7. Thus, these non-PCV7 serotypes would substitute for the eliminated vaccine strains and produce the same or greater incidence of AOM. More likely, the large 95% CI in the Finnish study was directly due to the small sample size, combined with the modest size of the relative risk reduction for AOM attributable to immunization with PCV7 [5]. In the California study, the large sample size narrowed the 95% CI and showed a 97% probability that the relative risk reduction was 5.2% [4].

The goal of this study was to evaluate the safety and efficacy of recombinant human DNase (rhDNase) in hospitalized patients with cystic fibrosis (CF) experiencing acute pulmonary exacerbations. Eighty patients with documented CF were enrolled at 11 CFcenters when admitted for antibiotic therapy. Patients were at least 5 yr old with a forced vital capacity (FVC)~ 35% of predicted and an oxygen saturation ~ 90% on a fraction of inspired oxygen (Flo2) < 0.5. Patients were randomized to receive rhDNase 2.5 mg in 2.5 ml excipient twice a day (n =43) or 2.5 ml excipient alone twice daily (n = 37) along with conventional treatment for exacerbations. Administration of rhDNase was not associated with acute adverse events or deaths, and no patients experienced allergic or anaphylactic reactions. Although forced expiratory volume in one second (FEV1) and FVC improved in both treatment groups during the double-blind period, there were no statistically significant differences in the mean change from baseline in FEV1 or FVC between the two groups. rhDNase therapy is safe and well tolerated in CFpatients with acute exacerbations requiring hospitalization, but the study did not demonstrate a statistically significant therapeutic effect of rhDNase when added to a regimen of antibiotics and chest physical therapy. Wilmott RW, Amln RS, Colin AA, DeVault A, DozorAJ, Elgen H, Johnson C, Lester LA, McCoy K, McKean LP, Moss R, Nash ML, Jue CP, Regelmann W, Stokes DC, Fuchs HJ. Aerosol­ Ized recombinant human DNase In hospitalized cystic fibrosis patients with acute pulmonary exacerbations.

Enteral formula feedings are frequently prescribed to cystic fibrosis (CF) patients to boost caloric intake. A substantial number of these patients are glucose intolerant and have severe respiratory compromise.To determine the effect of the carbohydrate content on glucose tolerance and respiratory function in glucose-intolerant CF patients with poor lung function, we examined the response to bolus feedings of five dietary supplements; a high-fat formula developed in our Clinical Research Center (CRC), Pulmocare, a high-carbohydrate formula developed in our CRC, Ensure Plus, and sugar-free Scandishake.Glucose excursion in response to the formulas with the lowest carbohydrate content was significantly less than that found in response to formulas with higher carbohydrate content. Insulin levels were also markedly lower in response to the low-carbohydrate high-fat formulas. Glucose excursion, expressed as a percent of the response to the CRC high-fat formula, was 111% +/- 12% for Pulmocare (p = NS), 202% +/- 34% for Ensure Plus (p01), 227% +/- 37% for CRC high carbohydrate (p = .001), and 357% +/- 33% for sugar-free Scandishake (p.001). CO2 production, O2 consumption, minute ventilation, and respiratory rate increased modestly but not significantly in response to all formulas. No significant differences were found between the formulas in regards to these parameters. There were no subjective complaints of dyspnea during any of the five studies.The carbohydrate content of liquid dietary supplements appears to be an important determinant of hyperglycemia in glucose-intolerant adult CF patients.

Increased numbers of eosinophils and increased concentrations of plasma proteins have been found in the airways of patients with mild asthma. We used an intact guinea pig trachea model to investigate the role of eosinophil peroxidase (EPO) in altering the function of the airway epithelial barrier. EPO in the presence of hydrogen peroxide (H(2)O(2)) and bromide (Br(-)) catalyzes the production of hypobromous acid (HOBr), which is felt to have a toxic effect on airway epithelial cells. An intact guinea pig trachea was mounted on an apparatus in a way that would allow the tracheal epithelium to be exposed to different solutions. Following these exposures, a test solution containing (14)C-sucrose (S), (3)H-inulin (I), and FITC-dextran-20 (D) was placed in the tracheal lumen and positioned in the center of the segment for 90 minutes. Flux of these molecules across the epithelial barrier into a bath was measured, and the permeability (P) was calculated for each molecule to quantify epithelial barrier function. Light and electron micrographic studies were performed to assess cellular damage. We found that there was a dose response to EPO (in the presence of fixed amounts of H(2)(O)(2) and Br(-)). EPO at 7.3 x 10(-7) M caused no increase in P over controls (Ringer's solution alone) for S, I, or D (P> 0.05), whereas EPO at 2.7 x 10(-6) M caused a significant increase in P over controls (P = 0.008) for all test molecules. Light and electron micrographs of the latter tracheas showed no evidence of microscopic changes despite the increased P. Further testing verified that the increase in permeability was caused by the EPO catalyzed reaction and not the individual substrates themselves, and that the reaction was inhibited by a peroxidase inhibitor. We conclude that EPO can alter the barrier function of the airway epithelium before gross cellular damage becomes visible. We hypothesize that changes in the tight junctions are responsible for the alteration in the barrier function of the airway epithelium and that this may play an important role in the pathophysiology of mild asthma.

The frequent recovery of Aspergillus species from the respiratory tract secretions of cystic fibrosis (CF) patients is well recognized, and the presence of the fungus in the airways may trigger an inflammatory response that can manifest as the clinical entity known as allergic bronchopulmonary aspergillosis (ABPA). In our CF patient population we studied the clinical characteristics of those who had Aspergillus sp. recovered from their respiratory tract secretions (n = 45) and compared them with the characteristics seen, during the same time period, in those patients who were culture negative for Aspergillus sp. (n = 167). There were no differences in peripheral blood eosinophil count (P = 0.9) or serum immunoglobulin E levels (P = 0.61). By logistic regression analysis there seemed to be an increased risk for more advanced lung disease, both radiographically (defined by a Brasfield chest radiograph score < 18) and by lung function parameters in those who were culture positive. However, after appropriate adjustment, almost all the increased risk was associated with age and gender, but not with the presence of Aspergillus sp. in respiratory secretions. Additionally, increasing age was strongly correlated with the risk of Aspergillus sp. being cultured from respiratory secretions (P = 0.0025). The presence of Aspergillus sp. in respiratory secretions was not associated with two indicators of atopy in our CF patient population. We do not have evidence that the culture of Aspergillus sp. from CF respiratory secretions is independently associated with an increased risk for more advanced lung disease.

Patients with cystic fibrosis (CF) of the same age differ significantly in their degree of pulmonary disease. Based on preliminary observations, we postulated that the activity of my-eloperoxidase would be significantly increased in patients with greater structural lung damage than in those with less lung damage. Acid extracts of weighed sputum samples were assayed for lactoferrin concentrations by ELISA. Activities of peroxidase, cathepsin G, and elastase (with and without proteinase 3) were determined by kinetic analysis using chromogenic substrates. The patients were divided into quartiles based on their Brasfield chest-radiograph score. Patients in the first quartile (least amount of structural lung abnormality) were compared to those in the fourth quartile. The concentration of lactoferrin, a specific (secondary) granule protein of neutrophils, did not differ between the two patient groups. However, the activities of the neutrophil primary granule proteins, peroxidase, elastase, and elastase plus proteinase 3, were significantly elevated in the group with the most structural lung abnormality. Sputum albumin concentration was used to estimate leakages of plasma proteins into the airways. Peroxidase activity, but not the activity of cathepsin G, of elastase, or of elastase plus proteinase 3, correlated significantly with albuminig sputum in both quartile groups. To confirm the association of sputum peroxidase activity with differences in lung structure and to test its correlation with lung function, spirometry was performed in a second group of patients during the week prior to the time of sputum sampling. In this second group, increased sputum peroxidase activity was associated with worse Brasfield scores and with decreased percent-predicted forced expiratory volume in 1 sec. Lactoferrin concentration again did not differ between the groups. Bacterial factors also did not differ. The results indicate that the degree of lung damage in patients with CF was more closely related to sputum peroxidase activity than to age, gender, CFTR genotype, or sputum bacterial parameters. Further study is required to determine whether or not peroxidase activity in the airway causes this lung damage. © 1995 Wiley-Liss, Inc.

Objectives To characterize the onset of persistent signs and symptoms of cystic fibrosis (CF) lung disease and identify characteristics that predict onset. Study design Patients in the Epidemiologic Study of CF who were

A standard definition of pulmonary exacerbation based on signs and symptoms would be useful for categorizing cystic fibrosis (CF) patients and as an outcome measure of therapy. The frequently used definition of treatment with intravenous antibiotics varies with practice patterns. One approach to this problem is to use large data sets which include a patient's signs and symptoms along with their clinician's decision to treat with antibiotics for the diagnosis of pulmonary exacerbation. Previous analysis of such a data set, the Epidemiologic Study of Cystic Fibrosis (ESCF), found that new crackles, increased cough, increased sputum, and weight decline were the four clinical characteristics most strongly influencing providers to treat young CF patients for a pulmonary exacerbation. The objectives of this study were to confirm that these four characteristics influence the decision to treat with antibiotics for a pulmonary exacerbation in young CF patients; to evaluate their implications for future nutritional status and lung function; and to assess the effect of antibiotic treatment on these characteristic signs and symptoms.This was an observational, longitudinal cohort study of clinical care in children6 years old cared for at sites participating in ESCF.Using data from children not included in the previous ESCF study, we confirmed that these four characteristics were significantly associated with the likelihood of physicians prescribing antibiotics to treat a pulmonary exacerbation. The number of these characteristics present at a single clinic visit before age 6 predicted hospitalization rate over the next year, the weight-for-age z-score, and the forced expiratory volume in 1 sec (FEV1) percent predicted at age 7. Treatment with antibiotics was associated with a greater decrease in the proportion of children with crackles, cough, and Pseudomonas aeruginosa at a follow-up visit within 6 months.New crackles, increased cough, increased sputum, and decline in weight percentile at a single clinic visit increase the risk of future malnutrition, hospitalization, and airflow obstruction in young children with CF. Treatment with antibiotics mitigates some of these signs and symptoms by the first follow-up visit. The presence of these four characteristic signs and symptoms is useful to define pulmonary exacerbations in young children with CF that respond to antibiotic treatment in the short-term and influence long-term prognosis.

BackgroundThe goal of this study was to determine the association of multiple antibiotic-resistant Pseudomonas aeruginosa (MARPA) acquisition with lung function decline in patients with cystic fibrosis (CF).MethodsUsing data from Epidemiologic Study of Cystic Fibrosis (ESCF), we identified patients with spirometry data and MARPA, defined as PA (1) resistant to gentamicin and either tobramycin or amikacin, and (2) resistant to ≥1 antipseudomonal beta lactam. MARPA had to be detected in a respiratory culture after ≥2years of PA-positive but MARPA-negative respiratory cultures. Multivariable piecewise linear regression was performed to model the annual rate of decline in forced expiratory volume in 1second (FEV1) % predicted 2 calendar years before and after the index year of MARPA detection, adjusting for patient characteristics and CF therapies.ResultsIn total, 4349 patients with chronic PA and adequate PFT data were identified; 1111 subsequently developed MARPA, while 3238 patients were PA positive but MARPA negative. Compared with patients who did not acquire MARPA, MARPA-positive patients had lower FEV1 and received more oral (p

Ode KL, Frohnert B, Laguna T, Phillips J, Holme B, Regelmann W, Thomas W, Moran A. Oral glucose tolerance testing in children with cystic fibrosis. Background: Cystic fibrosis (CF) related diabetes is the most common comorbidity in persons with CF. International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines recommend annual oral glucose tolerance testing (OGTT) screening starting at age 10. The OGTT might be recommended in younger children if, as in adults, it provided clinically relevant prognostic information. A database review was performed to determine whether OGTT findings in children with CF predict subsequent clinical course. Methods: A retrospective matched-pair cohort study was based on OGTTs performed during 1998–2003. Children aged 6–9 were classified as having normal glucose tolerance (NGT) or abnormal glucose tolerance (AGT). Children with AGT were matched by age and gender to those with NGT. Clinical status was assessed at baseline and 5 yr later. In a separate investigation, diabetes and prior AGT status of children aged 10–18 were used to assess predictions derived from the cohort study. Results: In 1998–2003, 39 of 94 children had AGT. Of these, 31 had sufficient follow-up data to be included. Both at baseline and 5 yr later there was no significant difference in height, weight, body mass index (BMI) or lung function between AGT and NGT. Diabetes developed in 13 AGT (42%) and one NGT (3%) [odds ratio (OR) 11, p = 0.0009]. Age of diabetes onset was 12 ± 1 yr in boys and 11 ± 1 yr in girls, compared to approximately 23 yr in the general CF population. Fifteen current children age 10–18 who had AGT before age 10 have diabetes, close to the prediction of 19. Conclusions: AGT in children with CF age 6–9 yr identifies those at high risk for progression to early onset diabetes.

Rationale Infant pulmonary function testing (IPFT) has become an important clinical tool for the evaluation of lung function in infants with Cystic Fibrosis (CF); however, it is still unclear whether lung function in infancy is predictive of lung function later in life. We hypothesized that measures of airflow obstruction by IPFT would correlate strongly with lung function by conventional spirometry later in childhood. Study Design and Methodology A retrospective analysis was performed of all CF infants studied with IPFT at the University of Minnesota Children's Hospital between September 1994 and March 2003. A total of 41 patients underwent IPFT and had valid spirometry results available at age 6 or later. IPFT values, such as I:E ratio, respiratory rate, tidal volume, and Tptef/Te, were calculated from tidal breathing loops. Passive respiratory system mechanics, which included Crs, Rrs, and τrs, were measured by the single breath end-inspiratory occlusion technique. Forced expiratory flows, including VmaxFRC, FVC, FEF50, and FEF75, were obtained by rapid thoracic compression and included a full vital capacity maneuver by the multiple inflation method. FRC measurements were calculated from data obtained via nitrogen washout in a subset of patients. In addition, information on age at diagnosis and results of oropharyngeal (OP) cultures at diagnosis and on subsequent visits was recorded. Standard spirometry was performed in all patients starting at age 5. The first valid flow-volume loop after age six was selected for analysis. Results Significant correlations were observed for the Rrs and the FEF50 by IPFT and the FEV1 and the FEF25–75 by standard spirometry (r > 0.4 and P

Freshly isolated monocytes from cystic fibrosis (CF) heterozygotes and homozygotes had significantly increased oxygen uptake and superoxide formation after surface glycoprotein stimulation than did monocytes from age- and sex-matched controls. Lack of differences among the genotypes in inhibition by simple sugars of the concanavalin A-stimulated superoxide production and lack of differences in concanavalin A-binding surface proteins suggested that different regulation of the oxidase pathway produced the increased oxygen uptake and superoxide formation in CF patients and carriers. This regulatory role is consistent with the predicted structure of the CF gene product. The results support the hypothesis that the mononuclear phagocytes of CF heterozygotes have a significantly increased ability to kill intracellular microbes and may confer a selective advantage to the host.

The incidence of methicillin resistant Staphylococcus aureus (MRSA) infection is increasing in cystic fibrosis (CF), but the impact of MRSA detection on clinical outcomes is unclear. Our objective was to determine whether incident detection of MRSA is associated with a change in pulmonary function over time in CF patients. We analyzed data from the Epidemiologic Study of Cystic Fibrosis (ESCF), a prospective observational study of CF patients in North America. Multivariable piecewise linear regression was used to model the impact of incident detection of MRSA on pulmonary function over time, measured by percent predicted forced expiratory volume in one second (FEV(1)% predicted), adjusting for potential confounders. There were 5,090 patientsor=6 years old who were MRSA negative for at least 2 calendar years. Five hundred ninety-three (12%) of these patients acquired MRSA during the years 2001-2003, with detection rates of MRSA during those years rising from 4.4% to 6.9%. MRSA positive patients had a lower FEV(1)% predicted and received more antibiotic and other therapies than patients who remained MRSA negative. After adjusting for antibiotic therapy and other potential confounders, MRSA positive patients also had a higher rate of decline in FEV(1)% predicted both before and after the incident culture, although the rate of FEV(1)% predicted decline did not change significantly after MRSA detection. In conclusion, although MRSA in CF was a marker for more aggressive therapy and may reflect increased disease severity, incident MRSA detection was not associated with a changing rate of FEV(1)% predicted decline.

Periodic fever syndrome is composed of a group of disorders that present with recurrent predictable episodes of fever, which may be accompanied by: (1) lymphadenopathy; (2) malaise; (3) gastrointestinal disturbances; (4) arthrolgia; (5) stomatitis; and (6) skin lesions. These signs and symptoms occur in distinct intervals every 4 to 6 weeks and resolve without any residual effect, and the patient remains healthy between attacks. The evaluation must exclude: (1) infections; (2) neoplasms; and (3) autoimmune conditions. The purpose of this paper is to report the case of a 41/2- year-old white female who presented with a history of periodic fevers accompanied by: (1) joint pain; (2) skin lesions; (3) rhinitis; (4) vomiting; (5) diarrhea; and (6) an unusual asymptomatic, marked, fiery red glossitis with features evolving to resemble geographic tongue and then resolving completely between episodes. This may represent the first known reported case in the literature of a periodic fever syndrome presenting with such unusual recurring oral findings.

The prevalence of methicillin resistant Staphylococcus aureus (MRSA) infections is increasing in both the general population and cystic fibrosis (CF) patients. We hypothesized that MRSA infection of the conductive airways as seen in CF would be associated with more severe disease than that seen with methicillin sensitive S. aureus (MSSA). To test this hypothesis, we used data from the Epidemiologic Study of Cystic Fibrosis (ESCF), a large observational study of CF patients in North America, to compare CF patients with MRSA in their respiratory tract cultures to those with MSSA. During a 1-year time period from January 1, 2001 to December 31, 2001, data from 20,451 patients were collected by the ESCF, and 1,834 (7.5%) patients had respiratory tract cultures that were positive for S. aureus only. Compared to patients with MSSA only, patients with MRSA only had significantly more airflow obstruction, as measured by forced expiratory volume in 1 sec (FEV1). The mean FEV1 for patients 6-17 years old with MRSA was 80.7% predicted compared to 89.4% in the MSSA group (P0.001). The likelihood of hospitalization and treatment with oral, inhaled, and intravenous antibiotics were all significantly increased in patients with MRSA compared to those with MSSA. Similar results were seen in patientsor=18 years old. The results of our study highlight the growing clinical impact of MRSA infections in CF patients.

Staphylococcus aureus is an important cause of pulmonary infections. The role of S. aureus α-toxin as a virulence factor is unclear. We hypothesized that airway epithelium is a target of S. aureus α-toxin and that exposure of airway epithelium to α-toxin results in damage to the airway epithelium. To examine the hypothesis that α-toxin is capable of independently producing airway epithelium damage as measured by permeability and morphometry, an isolated whole mouse trachea test apparatus was developed. In vitro epithelial permeability (P) was calculated and digital micrographs were analyzed morphometrically. Purified S. aureus α-toxin produced a significant increase in tracheal epithelial P (P

Excess neutrophils are present in the airways of patients with cystic fibrosis (CF). Myeloperoxidase (MPO) activity of acid extracts of sputum is directly correlated with airflow obstruction in CF patients. We hypothesized that the sputum MPO was derived from the MPO of neutrophils that entered the airways from the circulation. Active MPO without protease activity injures airways. If MPO activity from circulating neutrophils that emigrate into the airways of these patients causes increased airway epithelial permeability and mucus-gland secretion, then (1) those patients with greater MPO activity per circulating neutrophil would be more likely to produce sputum and (2) the MPO activity per circulating neutrophil would positively correlate with airflow obstruction. We determined the MPO activity for both circulating and sputum neutrophils. Spirometry and respiratory cultures were obtained simultaneously with blood and sputum samples. CF patients with more MPO activity within their circulating neutrophils were more likely to produce sputum ( P =.001, chi 2 test), and the MPO activity per circulating neutrophil was positively correlated with airflow obstruction as measured on the basis of the ratio of 1-second forced expiratory volume to forced vital capacity ( P

The clinical characteristics most relevant to the decision to treat for a pulmonary exacerbation with antibiotics in cystic fibrosis patients were determined. Variables including age, increased cough frequency and sputum production, new crackles and wheezing, asthma, symptomatic sinusitis, hemoptysis, decreased lung function, weight loss, and new acquisition of Pseudomonas aeruginosa were collected in a large prospective multicenter database (Epidemiologic Study of Cystic Fibrosis). During a 12-month baseline period, data from 11692 patients were compared with data collected during the subsequent 6-month study period. Because pulmonary function assessments were unavailable for patients6 years of age, separate analyses were done for those6 andor=6 years of age. The outcome of interest was any antibiotic treatment in the 6-month study period reported as indicated for an exacerbation. Characteristics with the most discriminatory power were determined using stepwise multiple logistic regression. For patients6 years of age, the strongest independent associations with treatment for a pulmonary exacerbation were new crackles, increased cough frequency, decline in weight, and increased sputum production. For those patientsor=6 years of age, the strongest independent associations were a relative decrease in percent predicted forced expired volume in 1 sec, increased cough frequency, new crackles, and hemoptysis. The presence of three or more of these key characteristics was strongly associated with the occurrence of a treated exacerbation. The reproducibility of the model over time was confirmed by application to a subsequent set of data. This model has potential for use as an outcome measure in clinical trials, and to assist in treatment decisions for individual patients.

A third generation, purified fusion protein (PFP-3) vaccine was developed to prevent severe respiratory syncytial virus (RSV) disease in high-risk groups. A phase II, multi-center, adjuvant-controlled trial was performed in RSV seropositive children with cystic fibrosis (CF); 151 received the adjuvant-control and 143 received the vaccine. Details of the vaccine-induced immune response are presented. At enrollment, RSV-specific, serum antibodies were comparable between both groups. A highly sensitive and specific serum antibody vaccine profile was established for the PFP-3 vaccine. At post-vaccination and end-of-study, RSV-specific, neutralizing antibody (Nt Ab) and binding antibody (Bd Ab) to the fusion (F) protein were significantly higher in PFP-3 vaccinees. After 28 days post-vaccination, Nt Ab and Bd Ab to F protein titers declined slowly at rates of 0.23 and 0.37 log2 per month, respectively. The PFP-3 vaccine-induced a robust immune response that lasted throughout the RSV season.

A major complication of hepatic cirrhosis is arterial hypoxemia, often the result of intrapulmonary arteriovenous shunting. While previously such hypoxemia was thought to preclude successful hepatic transplantation, more recent studies have suggested that hepatic transplantation should be considered if the hypoxemia is corrected by supplemental oxygen. We report the findings in a cirrhotic patient with severe hypoxemia associated with intrapulmonary arteriovenous shunting. The patient did not respond to supplemental oxygen (PaO2 < 40 mm Hg on O2 at 4 L/min). The patient underwent successful hepatic transplantation, with complete resolution of intrapulmonary shunting. We believe that patients with cirrhosis-associated intrapulmonary shunting, even with hypoxemia resistant to supplemental oxygen, are acceptable candidates for hepatic transplantation.

It is very important to note that safe and effective treatment of recurrent or persistent pneumonia in children is based on firmly establishing an etiologic diagnosis. Empiric treatment using repeated courses of antibiotics and hope is unlikely to yield cure or even good control of most of these processes and is likely to result in more cost to the patient's health and pocketbook. Applied in a staged and systematic way, the diagnostic tools currently available should enable the clinician caring for children to diagnose most of their patients with recurrent or persistent pneumonia. Consultation with a pediatric pulmonologist will generally speed the process and help with difficult or confusing cases. Because effective therapy is available but differs greatly from one etiology to another, early accurate etiologic diagnosis is extremely important. The prognosis for those with asthma generally is very good. But, delay in diagnosis of other causes of recurrent or persistent pneumonia can lead to irreversible pulmonary structural damage that ultimately can only be treated by lung transplantation, if at all.

To evaluate the significance of early bacteriologic findings in infants and younger children with cystic fibrosis, we divided patients identified at < or = 2 years of age into groups by initial oropharyngeal culture: group NF, normal respiratory flora (n = 17); group SA, Staphylococcus aureus without Pseudomonas aeruginosa (n = 20); group PA, P. aeruginosa without S. aureus (n = 6); group PA/SA, P. aeruginosa and S. aureus (n = 7); and group O, other potentially pathogenic bacteria (n = 31). Follow-up of patients ranged in age from 5.4 to 13 years. At diagnosis, group PA/SA had lower Brasfield scores (p < 0.02) and higher gamma-globulin levels (p < 0.03) than the other groups. Five years after diagnosis, Brasfield scores were significantly lower in groups PA and PA/SA compared with the other groups; mean gamma-globulin levels did not differ significantly among the groups. Groups PA and PA/SA also had evidence of significantly greater obstructive pulmonary disease by spirometry than groups NF and O. Group PA/SA had a 10-year survival estimate of 57%, significantly lower than the 92% to 100% estimates of the other four groups (p < 0.0001). Thus P. aeruginosa in initial oropharyngeal cultures from patients < or = 2 years of age with cystic fibrosis was associated with significantly increased morbidity, and the finding of P. aeruginosa and S. aureus together in initial oropharyngeal cultures with a significantly increased mortality rate during the first 10 years after diagnosis.

In 43 patients with cystic fibrosis, the results of 122 Tc-99m DTPA aerosol ventilation (DAV) studies were compared with pulmonary function tests (PFTs) that were performed within 24 hours of the DAV studies. The DAV studies were evaluated blindly for (A) number of pulmonary segments showing little or no ventilation, (B) number of foci of bronchial deposition of aerosol, and (C) subjective overall improvement, lack of change, or worsening from the previous study. (A) and (B) correlated significantly with all PFTs (p's < .001, r's = -.51 to -.73). Changes in (A) and (B) also correlated with changes in PFTs (p's < or = .001, r's = -.37 to -.58). The three populations in (C) were significantly different from each other with respect to changes in all PFTs (p < or = .002). Intervals between studies showing subjective improvement, no change, and worsening averaged 60, 133, and 306 days, respectively. These results suggest that DAV is an indicator of both regional and global pulmonary function and may be useful in evaluating patients with cystic fibrosis.

Thirteen patients with cystic fibrosis (aged 11 to 32 years) who were hospitalized for exacerbation and who had sputum cultures positive for Pseudomonas organisms were treated initially for 4 days with bronchodilators and physiotherapy followed by the addition of antibiotic (14 days, n = 8) or placebo (14 days, n = 4; 7 days, n = 1). Tc-99m DTPA aerosol scintigraphy was performed on the day before bronchodilators and physiotherapy, on the day before antibiotic or placebo, and on the day after completion of antibiotic or placebo therapy. Scintigrams were evaluated for change in the number of nonventilated segments and change in the number of bronchial deposits of aerosol. Sixty-nine percent of patients showed improvement after bronchodilators and physiotherapy alone. Sixty-two percent showed further improvement after antibiotic or placebo was added; this improvement was independent of whether antibiotic or placebo was administered (P greater than 0.1). These aerosol scintigraphy results failed to demonstrate that the effectiveness of bronchodilators and physiotherapy is enhanced by antibiotics in the treatment of cystic fibrosis exacerbations.

The susceptibility of paired mucoid and nonmucoid variants of Pseudomonas aeruginosa isolated from 13 patients with cystic fibrosis (CF) to killing by a 55,000-Da bactericidal protein (BP55) from human polymorphonuclear leukocytes was studied. Mucoid and nonmucoid variants were equally sensitive to killing by BP55 at both pH 5.6 and pH 7.2. Eleven of the isolates were resistant to the bactericidal activity of 10% normal human serum but were as sensitive as the serum-sensitive isolates to BP55. Similarly, the 15 isolates with lipopolysaccharides (LPS) containing O-polysaccharide side chains (smooth LPS) were as sensitive to BP55 as those isolates with rough LPS.P. aeruginosa isolates from patients in poor clinical condition were more likely to have LPS of the smooth type and to be resistant to killing by 10% human serum than the isolates from patients in good clinical condition. We have concluded that the susceptibility of the P. aeruginosa isolates from patients with CF to killing by BP55 does not correlate with mucoid or nonmucoid variations, with the presence or absence of smooth LPS, or with the sensitivity or resistance to killing by normal human serum.