Airway responsiveness in infants: Comparison of inhaled and nasally instilled methacholine

Airway responsiveness of infants is evaluated during sleep and the infants inhale the bronchial challenge agent via the nasal airway. Since stimulation of the nasal airway may produce bronchoconstriction, it is unclear whether the observed response in the infants results from deposition of the aerosol in the lower airways or from stimulation of nasal receptors. Therefore, in 6 healthy infants we compared the changes in partial expiratory flow-volume (PEFV) curves produced by aerosol inhalation of methacholine and the changes produced by instillation of equivalent doses of methacholine liquid into the nares. Following aerosol, the peak expiratory flow and the flow at functional residual capacity decreased, PEFV curves became concave in shape, and the oxygen saturation (Sa_o2) decreased. The highest methacholine concentration inhaled by any infant was 1.25 mg/mL. In contrast to aerosol delivery, a maximal methacholine concentration of 10.0 mg/mL was instilled into the nares of all 6 infants without any change in maximal flow at functional respiratory capacity (V_maxFRC) or Sa_o2. There was a significant decrease in peak flow and flattening of the PEFV curves at higher lung volumes; however, the PEFV curve remained convex in shape at the lower lung volumes. The changes in the PEFV curve following nasal instillation of methacholine are consistent with an increase in nasal resistance and no change in the lower airways. We conclude that the bronchoconstriction observed following inhaled methacholine does not result from stimulation of nasal receptors. Pediatr Pulmonol. 1993; 16:54–58. © 1993 Wiley-Liss, Inc.     

Heterogeneity of rabbit aortic endothelial cells, with special reference to phagocytosis.

Heterogeneity of aortic endothelial cells with regard to phagocytotic ability was examined by injecting India ink into normal rabbits. Light and electron microscopic analyses revealed that particles of India ink were phagocytosed in the endothelial cells, which in turn were localized at the distal side of the orifice of aortic branches, especially those of brachiocephalic, left clavicular, and dorsal intercostal arteries. No remarkable differences were found ultrastructurally between phagocytosing and nonphagocytosing endothelial cells. Ingested India ink particles were present within phagosomes of the endothelial cells for several hours after injection; the particles eventually accumulated in the subendothelial space twenty-four hours after injection. These results indicate that an active transport system of large molecules via the phagocytotic processes is present in endothelial cells located at the distal sides of the orifice of aortic branches. These regions are known to develop initial atherosclerotic lesions in hypercholesterolemic animals. Thus, a possible correlation between phagocytotic ability of endothelial cells and development of atherosclerosis is suggested.     

Anti-inflammatory effects of high-dose inhaled fluticasone versus oral prednisone in asthma exacerbations.

The objective of the present study was to investigate the kinetics of high doses of inhaled steroid fluticasone in comparison with oral steroid prednisone on plasma protein leakage and bronchial eosinophilia in adults with moderate asthma exacerbations. The study design was a randomised, double-blind, placebo-controlled prospective trial. In total, 45 patients treated at the emergency department for moderate asthma exacerbations were recruited and 39 were assigned to receive fluticasone and placebo of prednisone (19 patients), or prednisone and placebo of fluticasone (20 patients). Medication was administered to all patients via a metered-dose inhaler and spacer (16 puffs; 4,000 microg.day(-1) or placebo) plus one pill (prednisone 30 mg.day(-1) or placebo). Spirometry and induced sputum for differential cell counts, albumin and alpha(2)-macroglobulin levels and blood eosinophils, interleukin-5 and granulocyte-macrophage colony-stimulating factor levels were obtained before treatment and at 2, 6 and 24 h after treatment. Symptoms clearly improved after 24 h in both groups. No differences were seen between groups in peak expiratory flow or forced expiratory flow in one second, which improved progressively but then decayed slightly after 24 h. Eosinophil counts in sputum also improved over time in both groups. The effect was faster with fluticasone than with prednisone, but was partially lost at 24 h. However, plasma proteins in sputum and eosinophil count in blood both decreased until 24 h, with no significant differences between groups. There was no correlation between eosinophil counts and plasmatic protein levels. In conclusion, both treatments improved symptoms, airway obstruction and inflammation, and plasma protein leakage at 24 h. Prednisone reduced blood eosinophil counts, while fluticasone reduced airway eosinophil counts, suggesting that the anti-inflammatory performance of fluticasone is exerted locally.     

Effect of ozone on lysosomal enzymes of alveolar macrophages engaged in phagocytosis and killing of inhaled Staphylococcus aureus.

The role of lysosomal enzymes in the inactivation of inhaled bacteria by alveolar macrophages was studied in rats infected with aerosols of Staphylococcus aureus and then exposed for 5 hr to 2.5 ppm of ozone to determine whether pollutant-induced defects in phagocytic killing were associated with reduction in enzyme activity. Rates of bacterial ingestion and the activities of cellular acid phosphatase and beta-glucuronidase were measured simultaneously in in situ perfused right lungs by sequential staining of frozen sections for enzyme and bacteria. Quantitative measurements of enzyme activity within macrophages without ingested bacteria were made with a computer-controlled cytospectrophotometry system. Exposure to ozone resulted in diminished rates of bacterial clearance and ingestion, large increases in numbers of intra- and extracellular staphylococcal microcolonies, and an absence of enzyme activity for macrophages containing bacterial microcolonies. Enzyme activity was unimpaired in macrophages without ingested bacteria. These results, in which absence of enzyme activity occurred only in macrophages subjected to the dual insults of ozone exposure and ingested bacteria, prove a relationship between impairment in bactericidal capacity and cellular activities of lysosomal enzymes.     

Regular versus as-needed short-acting inhaled beta-agonist therapy for chronic obstructive pulmonary disease

Regular short-acting inhaled beta-agonist therapy is of uncertain benefit in patients with chronic obstructive pulmonary disease (COPD). We conducted a randomized, concealed, double-blind, placebo-controlled crossover trial in two periods, each of 3-mo duration, involving 53 patients with a smoking history of > 20 pack-years, an FEV1 of < 70% predicted, and an FEV1/VC ratio of < 0.7 after inhalation of 200 microg albuterol. All patients received regular ipratropium bromide at 20 microg per puff in 2 puffs four times daily, beclomethasone at 250 microg per puff or equivalent corticosteroid in 2 puffs twice daily, and open-label inhaled albuterol as needed. Interventional therapy consisted of regular inhaled albuterol (100 microg per puff, in 2 puffs four times daily) versus placebo. Patients used twice as much active albuterol in the regular use period (mean: 8.07 puffs of coded and 4.68 puffs of open-label medication; total: 12.75 puffs daily) than during the as-needed period (mean: 6.34 puffs of open-label albuterol daily). Despite greater beta-agonist use, patients showed similar results during treatment and control periods for all outcomes. Differences between active and placebo periods were: FEV1: -0.04 L (95% confidence interval [CI]: -0.09 to 0.01 L); slow vital capacity: 0.04 L (95% CI: -0.12 to 0.20 L); 6-min walk test distance: -3.1 m (95% CI: -16.8 to 10.5 m); and Chronic Respiratory Questionnaire scores for dyspnea: 0.02 (95% CI: -0.13 to 0.16); fatigue: -0.02 (95% CI: -0.25 to 0.20); mastery: 0.01 (95% CI: -0.20 to 0.24); and emotional function: 0.02 (95% CI: -0.20 to 0.24). We found that in patients with COPD, use of regular short-acting inhaled beta-agonists resulted in twice as much beta-agonist use without physiologic or clinical benefit as did use on an as-needed basis.     

Adherence to montelukast versus inhaled corticosteroids in children with asthma

Our objective was to compare adherence to montelukast with adherence to inhaled corticosteroids (ICS) in children with persistent asthma. In this retrospective study, we obtained data from a computerized hospital pharmacy database and medical records on 14l patients, 3-18 years of age, who received care for asthma at a military medical center. For each patient, we collected fill/refill data from a consecutive 6-month period and calculated an adherence rate, i.e., (# doses filled/# doses prescribed) x 100. We then determined whether the patient had "good adherence" (adherence rate, > or =70%) or "very poor adherence" (adherence rate, <50%). Eighty-one children were prescribed montelukast, and 104 took ICS; 44 of these children took both. The majority of patients had mild or moderate persistent asthma. There was no significant difference between mean adherence rates: 71% (95% CI, 65-77%) for montelukast vs. 67% (95% CI, 61-73%) for ICS. Fifty-one percent of patients taking montelukast had good adherence, compared to 41% in the ICS group (P = 0.27). Nineteen percent of the montelukast group and 26% of the ICS group had very poor adherence (P = 0.31). Using pharmacy refill data, we found that children with asthma were no more likely to take montelukast than inhaled corticosteroids. Adherence to both medications was suboptimal, even in a system that provides free and easy access to medications.     

Kinetic studies of phagocytosis.

The initial phagocytic rate of IgG coated polyvinyl toluene latex particles was assayed for isolated PMN cells. The kinetic studies of phagocytosis were performed in serum-free medium using an electronic particle counter. The mean phagocytic rate for the reference group of apparently healthy individuals was 0.60 min⁻¹. PMN cells from 5 of 26 patients with rheumatoid arthritis (RA) had subnormal values of particle ingestion rate, although the mean of the group was not significantly reduced compared to the controls. Correlation coefficient between the log of rheumatoid factor titer and phagocytic rate was 0.58 (P < 0.001). During penicillamine treatment an increased rate of phagocytosis was observed in patients with RA. Granulocytes isolated from 17 patients with systemic lupus erythematosus (SLE) had a significantly increased (P < 0.001) mean initial rate of phagocytosis (0.91 min⁻¹). Two patients in this group had an acute exacerbation of disease activity and were treated with large doses of prednisone. An appreciable decline in phagocytic rate was observed during the intensive corticosteroid therapy.     

Deposition and phagocytosis of inhaled particles in the gas exchange region of the duck, Anas platyrhynchos

Little is known about the fate of inhaled aerosol particles in birds; even the anatomical location of phagocytic cells within the lungs has yet to be clearly demonstrated. We exposed 2 anesthetized, spontaneously breathing ducks to a non-toxic iron oxide aerosol (aerodynamic mass mean diameter = 0.18 micron; 460 mg/m3) for 1.75 h and 2 awake, resting ducks to less concentrated aerosol (38 mg/m3) for 6 h on two consecutive days. All 4 ducks were sacrificed 24 h after the end of the last exposure. Their lungs, as well as the lungs from a control duck not exposed to the aerosol, were fixed in situ by insufflation of osmium tetroxide vapor or by intravascular perfusion. Then samples of the gas exchange region were examined with a transmission electron microscope. We found iron oxide particles: trapped within the trilaminar substance that is unique to avian lungs and coats the atria and infundibula; within epithelial cells of the atria and initial portions of the infundibula; and within interstitial macrophages. Only occasionally, small amounts of particles were found in the air capillaries. We conclude that both epithelial cells and interstitial macrophages can phagocytize particles in avian lungs, and that there is some convective transport of aerosol to the atria and the initial portions of the infundibula.     

A randomized open-label comparative study of montelukast versus theophylline added to inhaled corticosteroid in asthmatic children.

BACKGROUND: Inhaled corticosteroids (ICSs) are widely used in combination with other classes of drugs for treatment of childhood asthma. The efficacy and the safety of montelukast added to low-dose ICS therapy were compared with those of sustained-release theophylline added to low-dose ICS therapy in asthmatic children in the present study. METHODS: Following the 2-week run-in period, 6-to 14-year old patients receiving treatment with ICSs were randomized to treatment for 4 weeks with either montelukast 5 mg once daily or sustained release theophylline 5-8 mg/kg (dry syrup) or 100-200 mg (tablet) twice daily. Patients also received a fixed dose of ICS throughout the run-in and treatment periods. The primary efficacy endpoint was the change from baseline in peak expiratory flow (PEF) at Week 2. RESULTS: A significant increase in morning PEF was observed in the add-on montelukast group as compared with the add-on theophylline group at Week 2 (change from baseline of 22.8 L/minvs. 8.7 L/min; p = 0.041 for between-group difference) and at Week 4 (31.0 L/minvs. 9.8 L/min; p = 0.012). A significant increase in evening PEF was observed in the add-on montelukast group as compared with the add-on theophylline group at Week 4 (24.7 L/minvs. 8.7 L/min; p = 0.027). There were no significant differences between the treatment groups in incidences of clinical and laboratory adverse experiences. CONCLUSIONS: The results indicate that montelukast added to low-dose ICS is an effective and safe option for the treatment of asthma in children.     

Addition to inhaled corticosteroids of leukotriene receptor antagonists versus theophylline for symptomatic asthma: a meta-analysis

Background

Inhaled corticosteroids (ICSs) are widely used in combination with second controller medications in the management of asthma in adults and children. There lacks a systematic comparison between addition of leukotriene receptor antagonists (LTRAs) and theophylline to ICS. The purpose of this meta-analysis was to evaluate the difference of the efficacy and safety profile of adding either LTRAs or theophylline to ICS in adults and children with symptomatic asthma.

Methods

Randomised controlled trials (RCTs) published prior to November 2014 were acquired through systematically searching and selected based on the established inclusion criteria for publications. The data extracted from the included studies were further analyzed by a meta-analysis.

Results

We included eight RCTs, of which six recruited adults and two recruited children aged 5 to 14 years. The primary outcomes were changes in lung function from baseline, including forced expiratory volume in the first second (FEV₁) and peak expiratory flow (PEF). Overall, addition of LTRAs led to significantly better morning PEF {mean difference (MD) 16.94 [95% confidence interval (CI): 11.49-22.39] L/min, P<0.01} and FEV₁ [MD 0.09 (95% CI: 0.03-0.15) L, P=0.005] as compared to addition of theophylline. There were no differences between the two treatments in terms of evening PEF, adverse events, rescue medication use and asthma exacerbation.

Conclusions

The combination of LTRA and ICS leads to modestly greater improvement in lung function than the combination of theophylline and ICS in the treatment of symptomatic asthma. Long-term trials are required to assess the efficacy and safety of these two therapies.     

Structural requirements of Syk kinase for Fcgamma receptor-mediated phagocytosis.

The tyrosine kinase Syk plays a critical role in the phagocytic pathway mediated by Fcgamma receptors (FcgammaR). In transfected COS1 cells co-expression of Syk enhances FcgammaR mediated phagocytosis. The other member of the Syk kinase family, the highly homologous tyrosine kinase Zap70, also plays a role in signaling by immunoglobulin gene family receptors, but does not increase the phagocytic efficiency of FcgammaRs. The homologous tandem SH2 and kinase domains of Syk and Zap70 are separated by a nonhomologous region referred to as the unique domain. Zap70's inability to enhance phagocytosis was not due to unique domain tyrosine 292, previously implicated in negative regulation of Zap70 function. We determined the regions of Syk important for its interaction with the phagocytic pathway. An intact kinase domain was required for Syk's effect on phagocytosis. Furthermore, the Syk variant SykB, lacking 23 amino acids in the unique region, signaled for phagocytosis as efficiently as did Syk. We then constructed exchange chimeras between Syk and Zap70 and determined the contributions of the SH2, unique and kinase domains to phagocytic signaling. Our data suggest that the Syk kinase domain, which has high intrinsic kinase activity, is important for facilitating phagocytic signaling by FcgammaRI and FcgammaRIIIA.     

Montelukast versus inhaled corticosteroids in the management of pediatric mild persistent asthma

Background

Lung tissue of patients with acute respiratory distress syndrome (ARDS) is heterogeneously damaged and prone to develop atelectasis. During inflation, atelectatic regions may exhibit alveolar recruitment accompanied by prolonged filling with air in contrast to regions with already open alveoli with a fast increase in regional aeration. During deflation, derecruitment of injured regions is possible with ongoing loss in regional aeration. The aim of our study was to assess the dynamics of regional lung aeration in mechanically ventilated patients with ARDS and its dependency on positive end-expiratory pressure (PEEP) using electrical impedance tomography (EIT).

Methods

Twelve lung healthy and twenty ARDS patients were examined by EIT during sustained step increases in airway pressure from 0, 8 and 15 cm H₂O to 35 cm H₂O and during subsequent step decrease to the corresponding PEEP. Regional EIT waveforms in the ventral and dorsal lung regions were fitted to bi-exponential equations. Regional fast and slow respiratory time constants and the sizes of the fast and slow compartments were subsequently calculated.

Results

ARDS patients exhibited significantly lower fast and slow time constants than the lung healthy patients in ventral and dorsal regions. The time constants were significantly affected by PEEP and differed between the regions. The size of the fast compartment was significantly lower in ARDS patients than in patients with healthy lung under all studied conditions.

Conclusion

These results show that regional lung mechanics can be assessed by EIT. They reflect the lower respiratory system compliance of injured lungs and imply more pronounced regional recruitment and derecruitment in ARDS patients.     

Addition of montelukast versus double dose of inhaled budesonide in moderate persistent asthma

BACKGROUND: Although current guidelines suggest the use of inhaled corticosteroids as the first line therapy in persistent asthma, the concerns about high-dose corticosteroids may limit their usage. We aimed to investigate the efficacy of inhaled budesonide plus oral montelukast versus a double dose of inhaled budesonide. METHODOLOGY: Thirty patients with moderate asthma took part in the study. Following a 2-week run in period, the patients were randomized into two groups to receive 400 microg/day of inhaled budesonide plus 10 mg/day of montelukast (BUD + M group) or 800 microg/day of inhaled budesonide (high BUD group). The patients were evaluated at 2-week intervals (during a total treatment period of 6 weeks) for symptom scores, asthma exacerbations, lung function, use of short-acting beta2 agonist, blood eosinophil counts and adverse events. RESULTS: At the end of the study, morning and daytime symptom scores were significantly reduced within the groups. Although there was a significant decrease in the frequency of short-acting beta2 agonist use in the BUD + M group, the decrease in the high BUD group was not significant. During the study period, no patient in either group experienced an asthma exacerbation. Blood eosinophil levels significantly declined in both the BUD + M (0.87 +/- 0.31%) and high BUD groups (0.67 +/- 0.29%) as compared with baseline levels (BUD + M = 2.60 +/- 0.65%, high BUD group = 2.60 +/- 0.47%; P < 0.05). CONCLUSION: Our results suggest that the addition of montelukast to low-dose inhaled budesonide is as effective as a double dose of inhaled budesonide in asthma control.     

Effectiveness of inhaled bronchodilator delivery systems for elderly patients.

A prospective study of inhaler technique using aerosol metered dose inhalers (MDIs), Rotahalers and a breath-activated device (Aerolin Autohaler) was undertaken to assess how effectively elderly patients use their inhalers. Fifty-one patients aged 67-89 years (mean 77.4 years) were enrolled. Peak flow, FEV1 and FVC were recorded, before and after inhalation of 2.5 mg of salbutamol via a nebulizer, to assess the extent of reversible airways obstruction. Inhaler technique was assessed using a scoring system, based on performance in five aspects of inhaler use. Those with poor technique were randomly allocated to an alternative inhaler and reassessed. Twenty-nine of 51 patients demonstrated reversibility in their airways disease. Twenty-one of 47 had poor technique using an MDI and were given Rotahaler or Aerolin devices to use. Ten of 11 given Aerolin Autohalers improved but seven of ten using Rotahaler showed no improvement (p = 0.006). Subsequently, five of these seven were able to improve their technique with the breath-activated autohaler. The breath-activated Aerolin Autohaler is a better delivery system than Rotahalers for inhaled bronchodilators for elderly patients.