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Biomedical subjects

Philip E Silkoff

Publications and source records attributed to Philip E Silkoff.

At least 19 recordsLinked to original sources
PubMed2006

A simple technique to characterize proximal and peripheral nitric oxide exchange using constant flow exhalations and an axial diffusion model.

The most common technique employed to describe pulmonary gas exchange of nitric oxide (NO) combines multiple constant flow exhalations with a two-compartment model (2CM) that neglects 1) the trumpet shape (increasing surface area per unit volume) of the airway tree and 2) gas phase axial diffusion of NO. However, recent evidence suggests that these features of the lungs are important determinants of NO exchange. The goal of this study is to present an algorithm that characterizes NO exchange using multiple constant flow exhalations and a model that considers the trumpet shape of the airway tree and axial diffusion (model TMAD). Solution of the diffusion equation for the TMAD for exhalation flows >100 ml/s can be reduced to the same linear relationship between the NO elimination rate and the flow; however, the interpretation of the slope and the intercept depend on the model. We tested the TMAD in healthy subjects (n = 8) using commonly used and easily performed exhalation flows (100, 150, 200, and 250 ml/s). Compared with the 2CM, estimates (mean +/- SD) from the TMAD for the maximum airway flux are statistically higher (J'aw(NO) = 770 +/- 470 compared with 440 +/- 270 pl/s), whereas estimates for the steady-state alveolar concentration are statistically lower (CA(NO) = 0.66 +/- 0.98 compared with 1.2 +/- 0.80 parts/billion). Furthermore, CA(NO) from the TMAD is not different from zero. We conclude that proximal (airways) NO production is larger than previously predicted with the 2CM and that peripheral (respiratory bronchioles and alveoli) NO is near zero in healthy subjects.

Adult↗
PubMed2005

Exhaled nitric oxide identifies the persistent eosinophilic phenotype in severe refractory asthma.

BACKGROUND: The fractional concentration of exhaled nitric oxide (FENO) is increased in asthma, correlates with eosinophilic inflammation, and decreases after steroid therapy. OBJECTIVE: We sought to examine whether persistent eosinophilia would be accompanied by an increased FENO level despite steroid therapy in patients with severe refractory asthma (SRA) as manifestations of steroid resistance. METHODS: Subjects with SRA, subjects with mild-moderate asthma, and healthy control subjects had FENO measured, followed by endobronchial biopsy and bronchoalveolar lavage. Tissue and bronchoalveolar lavage inflammatory cells were assessed for all subjects, and eosinophil status (EOS+/EOS-) was determined for subjects with SRA. RESULTS: Twenty-four subjects with SRA, 15 subjects with moderate-mild asthma, and 17 healthy control subjects were studied. Subjects with EOS+ SRA had significantly higher median FENO levels compared with levels in subjects with EOS- SRA (P = .0084) and all other groups. In subjects with SRA, FENO levels correlated with tissue eosinophils (r(s) = 0.54, P = .007), lymphocytes (r(s) = 0.40, P = .003), and mast cells (r(s) = 0.44, P = .05). FENO levels of greater than 72.9 ppb were associated with a sensitivity of 0.56 and a specificity of 1.0 for EOS+ status in subjects with SRA. CONCLUSION: FENO measurement identified the subgroup of subjects with SRA with persistent eosinophilia despite steroid therapy. Further studies are needed on the use of FENO to monitor response to therapy over time in subjects with SRA.

Adult↗
PubMed2005

Winter air pollution and disease parameters in advanced chronic obstructive pulmonary disease panels residing in Denver, Colorado.

BACKGROUND: Ambient pollution might worsen chronic obstructive pulmonary disease (COPD). OBJECTIVE: We explored the associations of pollution to pulmonary function, rescue medication, and symptoms over 2 winters in 2 panels of subjects with advanced COPD in Denver, Colorado. METHODS: Subjects measured lung function and recorded symptoms and rescue medications. Daily ambient pollution concentrations for particulate matter (PM(10) and PM(2.5)), carbon monoxide (CO), and nitrogen dioxide (NO(2)) were obtained for Denver. Estimated effects of pollution on outcomes were derived for the same day and 1 and 2 days after pollution measurements (lags 0, 1, and 2, respectively). RESULTS: Sixteen (mean age, 65.8 years; mean FEV 1 , 42.3% of predicted value) and 18 (mean age, 67.4 years; mean FEV 1 , 39.4% of predicted value) subjects participated in the first and second winters, respectively. There were no differences in demographic or disease characteristics between the 2 panels. In the first winter no detrimental associations were found. In the second winter, however, there were significant detrimental associations of CO in the morning and PM(10), CO, and NO(2) in the evening, increasing medication use at lag 0. Total symptom score increased at lag 0 with NO(2). The concentrations of particulates were increased in the second winter compared with in the first winter, and this winter was colder and more humid. CONCLUSIONS: In the second winter, subjects with severe COPD had worse lung function at lags 0 and 1 and increased rescue medication at lag 0 with increases in ambient air pollution. The effects of pollution varied between the 2 winters, perhaps related to levels of pollution and weather patterns. Significant effects were seen despite ambient pollution levels that conformed to US Environmental Protection Agency standards.

Aged↗
PubMed2005

Objective monitoring of nasal airway inflammation in rhinitis.

Allergic rhinitis is an inflammatory nasal disorder in which a range of different cells participates. A variety of approaches has been used to monitor nasal inflammation objectively to investigate disease processes and to evaluate the effect of therapeutic intervention. These approaches include nasal lavage, nasal cytology, and nasal biopsy, together with the more recently established measurement of nasal nitric oxide (NO) concentration. Although all provide information about nasal mucosal inflammation, the extent of information that can be obtained by each approach, the ease of sampling, and the complexity of sample handling differ. Such considerations influence the choice of approach when measurement of nasal inflammation is to be an objective outcome parameter in a clinical trial. In addition, the choice of approach is also determined by the questions or hypotheses that are to be addressed. Nasal lavage is simple and rapid to perform, is well tolerated, and provides a sample that can provide information about luminal cell recruitment, cell activation, and plasma protein extravasation. Nasal cytology involves sampling and recovering mucosal surface cells. It is also easy to perform and is well tolerated in general, although some find that the procedure causes a transient unpleasant sensation. A differential cell count from the sample provides information about relative cell populations. Both nasal lavage and nasal cytology are readily applicable to clinical trials. Nasal cytology sample handling is easier, but nasal lavage offers the advantage of providing considerably greater information from the sample. Nasal biopsy is a considerably more invasive procedure and requires expertise not only in tissue sampling but also in biopsy processing. Therefore, it is applicable only in specialist centers. However, nasal biopsy is the only sampling technique that directly informs about tissue cellular events, although these may be implied, in part from the other sampling approaches. Tissue specimens can be used to evaluate both protein and gene expression. Measurement of nasal NO involves expensive equipment but provides an instantaneous result, unlike the other approaches, all of which require sample processing and analysis. Recommendations for standardization of measurement have been made, and measures are considered in part to reflect allergic inflammation within the nasal mucosa. The limitations of nasal NO are that it reflects only a certain aspect of allergic mucosal inflammation, and that because a proportion of nasally measured NO is derived from the sinuses under normal circumstances, nasal NO is not specific for nasal disease. The high contribution from the sinus mucosa limits the discriminatory ability of nasal NO to reflect nasal tissue-specific alterations. The incorporation of measures of nasal inflammation in clinical trials has distinguished anti-inflammatory therapy from symptomatic therapy and has the potential to provide information about the efficacy of novel therapies for allergic rhinitis.

Biomarkers↗
PubMed2005

Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years.

BACKGROUND: Fractional exhaled nitric oxide (FE NO ) is used in monitoring of asthma. OBJECTIVES: The aim of this multicenter study was to establish normal values of FE NO and assess feasibility in children with a standardized method and equipment approved for clinical use. METHODS: FE NO was measured in healthy subjects of 4 to 17 years according to American Thoracic Society guidelines (single breath online, exhalation flow 50 mL/s) with a chemiluminescence analyzer (NIOX Exhaled Nitric Oxide Monitoring System, Aerocrine, Sweden) in 3 European and 2 US centers. Each child performed 3 acceptable nitric oxide measurements within 6 attempts and completed an extended International Study of Asthma and Allergy in Children questionnaire. RESULTS: Measurement of FE NO was attempted in 522 children. Four hundred five children completed the study according to the protocol. Geometric mean FE NO in 405 children was 9.7 ppb, and the upper 95% confidence limit was 25.2 ppb. FE NO increased significantly with age, and higher FE NO was seen in children with self-reported rhinitis/conjunctivitis or hay fever. The success rate was age-dependent and improved from 40% in the children 4 years old to almost 100% from the age of 10 years. The repeatability of 3 approved measurements was 1.6 ppb (95% CI, 1.49-1.64 ppb). CONCLUSION: FE NO in healthy children is below 15 to 25 ppb depending on age and self-reported atopy. Measurement of FE NO by NIOX is simple and safe and has a good repeatability. Feasibility depends on age and may be difficult in the preschool child.

Adolescent↗
PubMed2005

Hydrofluoroalkane-134A beclomethasone or chlorofluorocarbon fluticasone: effect on small airways in poorly controlled asthma.

Inflammation in asthma extends into the small airways (< 2 mm diameter). Most inhaled corticosteroids are suspensions with a particle size > 2 mm. Therefore, inflammation in the small airways of patients with asthma may not be adequately treated with these preparations. Some inhaled corticosteroids, on the other hand, are compounded with alcohol, resulting in a solution producing an aerosol that has a mean particle diameter of < 2 mm. This study was designed to compare the addition of equivalent amounts of two inhaled corticosteroids (one a suspension and one a solution) to the treatment of patients with asthma, which was uncontrolled despite treatment with moderate to high doses of inhaled corticosteroids and usually additional controller medications. The study was performed with 30 patients, > or = 18 years of age. Subjects were randomized in a single-blind fashion to receive, in addition to their current asthma therapy, either CFC-FP 220 microg each morning and 110 microg each evening (n = 10) or HFA-BDP 160 mcg twice daily (n = 20). Pre- and postbronchodilator spirometry, single breath nitrogen washout for closing volume and residual volume by plethysmography were assessed before and after 3 months of therapy. In the subjects who received HFA-BDP, the ratio of closing volume (CV) to vital capacity (VC) and residual volume (RV) decreased significantly (p = 0.0214 and 0.0433, respectively), whereas forced expiratory flow over 25-75% of the vital capacity (FEF25-75%), forced expiratory volume in 1 second (FEV1), and morning peak flow improved significantly (p = 0.0014, 0.0184, and 0.0321). Improvements from baseline of CV, CV/VC, and postbronchodilator FEF25-75%, were statistically significant in the HFA-BDP group compared with the CFC-FP group (p = 0.0049, 0.0194, and 0.0355, respectively). These preliminary findings suggest that the addition of HFA-BDP, compared with CFC-FP in patients with poorly controlled asthma despite receiving moderate to high doses of inhaled steroids, has a greater effect on parameters reflecting small airway patency presumably secondary to reduction in inflammation.

Administration, Inhalation↗
PubMed2004

NO pathway in CF and non-CF children.

Controversy exists concerning abnormalities of the nitric oxide (NO) pathway in cystic fibrosis (CF) lung disease. Although some studies suggested that NO activity is impaired in CF, changes in NO production in young children have not been studied. We hypothesized that nitric oxide synthase (NOS II) expression is decreased in young children with CF, leading to decreased production of lower airway NO, and that decreased NOS II expression is related to airway inflammation. Accordingly, we measured lower airway exhaled NO, nitrate, and NOS II expression in airway epithelium and macrophages by bronchoscopy, bronchoalveolar lavage (BAL), and bronchial brushing in 13 children with CF, 4 adolescent patients with CF, and 14 disease control children. Lower airway NO and nitrate were not different between CF and disease controls. Immunostaining studies of NOS II expression in airway epithelial cells and macrophages were similar in CF and control patients. Within the CF group, however, expression of NOS II was inversely related to BAL neutrophil counts and IL-8, two markers of airway inflammation. We conclude that lower airway NO, nitrate levels, and NOS II expression are not different in young children with CF and disease control patients, but that NOS II expression decreases in CF as airway inflammation increases.

Adolescent↗
PubMed2004

Single-breath exhaled nitric oxide in preschool children facilitated by a servo-controlled device maintaining constant flow.

Fractional concentration of exhaled nitric oxide (FENO), an index of airway inflammation, is optimally measured in adults and school-age children using a single-breath online (SBOL) exhalation at constant flow. However, preschool-aged (<6 years old) children have difficulty exhaling at constant flow, and alternative methods are needed. We employed a servo-controlled variable resistance device (servo device) that controls expiratory flow while allowing the child to vary expiratory pressure. To validate this device, 8 children (aged 6-12 years) performed SBOL exhalations with and without the servo device at expired flow rates between 20-50 ml/sec. We then studied 32 young children aged 24-71 months with the servo device alone at exhalation flows of 30, 40, and 50 ml/sec. Test difficulty (TD) with each method was rated by questioning the older children, or as observed by the physician obtaining the data in the younger children (0 = no difficulty, 1 = mild difficulty, 2 = moderate difficulty, and 3 = unable to perform test). In the older children, SBOL exhalations with and without the servo device demonstrated equivalent flow-dependence of FENO values. Test difficulty was low (0.125-0.625) at all flow rates, with excellent agreement between the two methods (P < 0.001). Twenty-eight young children (<6 years old) were able to complete measurements at all three flow rates evaluated. The 4 subjects who were not able to successfully complete all the measurements were between 2-3 years old (mean 2.75 +/- SD). Exhaled NO (mean +/- SD; ppb) was 8.8 (+/-6.2), 10.6 (+/-6.7), and 13.2 (+/-8.8) ppb at flows of 50 ml/sec, 40 ml/sec, and 30 ml/sec, respectively. Mean values of SD scores were 1.00, 1.14, and 1.43 at flows of 50, 40, and 30 ml/sec, respectively (P = NS). In conclusion, exhaled NO measurement by the SBOL method was facilitated in preschool children by the use of a servo-controlled variable resistance device. This device may allow these measurements to be applied to aid in the diagnosis and treatment of asthma in the preschool child, where spirometry is generally impossible.

Age Factors↗
PubMed2004

Safety and application of induced sputum analysis in childhood asthma.

BACKGROUND: The value of sputum induction in pediatric asthma lies in its potential to directly and noninvasively assess airway inflammation in children, because bronchoscopy and biopsy carry some risk. The Childhood Asthma Management Program (CAMP) study was designed to evaluate the long-term effects of budesonide and nedocromil compared with placebo in children with mild to moderate asthma across 8 centers. OBJECTIVE: At the Denver CAMP site, we sought to evaluate the safety of sputum induction, to determine differences in airway inflammation between treatment groups by using induced sputum analysis, and to examine correlations between other biomarkers and sputum eosinophils. METHODS: Sputum induction was performed, and exhaled nitric oxide, circulating eosinophil counts, and serum eosinophil cationic protein were obtained at treatment discontinuation and after washout. Spirometry and a methacholine challenge were also performed according to the CAMP protocol. RESULTS: Ninety of 117 children provided an adequate sputum sample for analysis. In 9 subjects (3 nedocromil and 6 placebo), sputum induction resulted in bronchospasm. These subjects had greater disease severity, as measured by a lower median prebronchodilator FEV 1 percentage predicted (85.0% vs 96.0%; P =.024) and FEV 1 /FVC ratio (70.0% vs 79.0%; P =.0008); greater bronchodilator reversibility (16.5% vs 6.8%; P =.004); higher serum IgE (1390.0 vs 495.0 ng/mL; P =.017) and circulating eosinophil count (757.0 vs 282.0/mm 3; P =.04); greater use of prednisone (1.9 vs 0.9 courses per 100 person-years; P =.05); and greater supplemental inhaled steroid doses (85.3 vs 0 mg; P =.016). At treatment discontinuation, budesonide-treated patients had a lower median (1st, 3rd quartile) sputum percentage eosinophil (SPEos) (0.2% [0%, 1.2%] vs 0.8% [0.2%, 4.6%]; P =.03) compared with those treated with placebo; no significant difference was noted between nedocromil- and placebo-treated patients. Higher SPEos at the time of treatment discontinuation was associated with asthma worsening that required rescue prednisone (n = 23) during the washout period compared with patients who remained stable (3.6% [0.4%, 6.4%] vs 0.6% [0.2%, 3.2%] SPEos; P =.023). Finally, greater SPEos was associated with atopy, higher bronchodilator reversibility, lower FEV 1 /FVC ratio, higher exhaled nitric oxide levels, circulating eosinophils, sputum and serum eosinophil cationic protein, more prednisone courses during the treatment period, and greater asthma severity. CONCLUSIONS: Sputum induction is a relatively noninvasive and safe procedure that can provide information on eosinophilic inflammation and treatment response and is also associated with several measures of asthma control. However, this procedure still remains a research tool in asthma because of its requirements for technical expertise.

Adolescent↗
PubMed2004

The Aerocrine exhaled nitric oxide monitoring system NIOX is cleared by the US Food and Drug Administration for monitoring therapy in asthma.

The Aerocrine exhaled nitric oxide (NO) monitoring system NIOX was cleared by the US Food and Drug Administration for clinical application in patients with asthma in May 2003. The fractional concentration of exhaled NO has been extensively researched as a marker of airway inflammation in asthma and other diseases and is now poised to enter clinical application. The American Thoracic and European Respiratory Societies' current guidelines recommend measurement at constant expiratory flow, which is difficult for some adults and children. The NIOX NO monitoring system was designed to facilitate standardized measurement according to guidelines. A clinical study was performed together with in vitro testing to obtain clearance. Exhaled NO levels were measured in unstable steroid-naive adult and pediatric asthmatic subjects and again after a 2-week treatment with inhaled corticosteroids. Exhaled NO levels decreased highly significantly, with 95% confidence limits for the decrease of -40% to -60% accompanied by clinical improvement. This trial, together with extensive in vitro testing, led to the clearance of NIOX by the US Food and Drug Administration. This article in the journal's "New products" feature section will describe background material regarding exhaled NO, special features of the NIOX NO monitoring system, and how this tool can be incorporated into clinical asthma management.

Adolescent↗
PubMed2004

Modeling pulmonary nitric oxide exchange.

Nitric oxide (NO) was first detected in the exhaled breath more than a decade ago and has since been investigated as a noninvasive means of assessing lung inflammation. Exhaled NO arises from the airway and alveolar compartments, and new analytical methods have been developed to characterize these sources. A simple two-compartment model can adequately represent many of the observed experimental observations of exhaled concentration, including the marked dependence on exhalation flow rate. The model characterizes NO exchange by using three flow-independent exchange parameters. Two of the parameters describe the airway compartment (airway NO diffusing capacity and either the maximum airway wall NO flux or the airway wall NO concentration), and the third parameter describes the alveolar region (steady-state alveolar NO concentration). A potential advantage of the two-compartment model is the ability to partition exhaled NO into an airway and alveolar source and thus improve the specificity of detecting altered NO exchange dynamics that differentially impact these regions of the lungs. Several analytical techniques have been developed to estimate the flow-independent parameters in both health and disease. Future studies will focus on improving our fundamental understanding of NO exchange dynamics, the analytical techniques used to characterize NO exchange dynamics, as well as the physiological interpretation and the clinical relevance of the flow-independent parameters.

Animals↗
PubMed2004

Exhaled nitric oxide in children with asthma receiving Xolair (omalizumab), a monoclonal anti-immunoglobulin E antibody.

OBJECTIVE: To evaluate the effect of a humanized monoclonal antibody to immunoglobulin E, omalizumab (Xolair, Novartis Pharmaceuticals, East Hanover, NJ; Genentech Inc, South San Francisco, CA), on airway inflammation in asthma, as indicated by the fractional concentration of exhaled nitric oxide (FE(NO)), a noninvasive marker of airway inflammation. Xolair was approved recently by the US Food and Drug Administration for moderate-to-severe allergic asthma in adolescents and adults. STUDY DESIGN: As an addendum at 2 sites to a randomized, multicenter double-blind, placebo-controlled trial, FE(NO) was assessed in children with allergic asthma over 1 year. There were 3 consecutive study periods: 1) stable dosing of inhaled beclomethasone dipropionate (BDP) when the dose was optimized (period of 16 weeks); 2) inhaled steroid-reduction phase (period of 12 weeks), during which BDP was tapered if subjects remained stable; and 3) open-label extension phase, during which subjects receiving placebo were switched to active omalizumab (period of 24 weeks). The primary outcome was area under the FE(NO) versus time curve (AUC) for adjusted FE(NO), defined as the ratio of FE(NO) at each time point compared with the value at baseline. RESULTS: Twenty-nine subjects participated and were randomized to omalizumab (n = 18) and placebo (n = 11) treatment groups in a 2:1 ratio dictated by the main study. There was a significant difference for age, resulting in a difference in absolute forced expiratory volume in 1 second but no difference in asthma severity based on the forced expiratory volume in 1 second percentage predicted. Baseline BDP dose was comparable between groups, as were baseline values of mean FE(NO) (active: 38.6 +/- 25.6 ppb; placebo: 52.7 +/- 52.9 ppb). The degree of BDP dose reduction during the steroid-reduction and open-label phases was equivalent between the omalizumab and placebo-treated groups; subjects in the omalizumab- and placebo-treated groups had reduced their BDP dose by an average of 51% and 60%, respectively, at the end of the steroid-reduction phase and by 68% and 94%, respectively, by the end of the open-label period. In the active and placebo groups, 44% and 27% and 75% and 73% of subjects had stopped use of inhaled corticosteroids at the end of the steroid-reduction and open-label phases, respectively. There was no significant difference between the active and placebo groups during the steroid-stable phase for AUC of adjusted nitric oxide (1.31 +/- 1.511 vs 1.45 +/- 0.736). However, during the steroid-reduction phase, the variability of adjusted FE(NO) in the placebo-treated group was greater than that of the omalizumab-treated group at most visits, with a significant difference between groups for AUC of adjusted nitric oxide (0.88 +/- 0.69 vs 1.65 +/- 1.06). FE(NO) fell from 82.1 +/- 55.6 ppm at the end of the steroid-reduction phase to 33.3 +/- 21.6 ppb at the end of the open-label period in the placebo group who were placed on active omalizumab. This decrease occurred while the mean dose of BDP remained very low. Analysis of FE(NO) over 52 weeks of omalizumab treatment in the active group demonstrated that there was a significant reduction from baseline to the end of the open-label period (41.9 +/- 29.0 to 18.0 +/- 21.8 ppb) despite a high degree of steroid reduction. CONCLUSION: In this preliminary study based on FE(NO), a noninvasive marker of airway inflammation, treatment with omalizumab may inhibit airway inflammation during steroid reduction in children with allergic asthma. The degree of inhibition of FE(NO) was similar to that seen for inhaled corticosteroids alone, suggesting an antiinflammatory action for this novel therapeutic agent in asthma. This is in keeping with recent evidence that omalizumab inhibits eosinophilic inflammation in induced sputum and endobronchial tissue.

Anti-Asthmatic Agents↗