Re: membranous obliterative bronchitis: a proposed unifying model.
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Bronchiectasis↗
Biomedical subjects
M L Everard
Publications and source records attributed to M L Everard.
Differentiation and immune function of human dendritic cells following infection by respiratory syncytial virus.
RSV causes annual epidemics of bronchiolitis in winter months resulting in the hospitalization of many infants and the elderly. Dendritic cells (DCs) play a pivotal role in coordinating immune responses to infection and some viruses skew, or subvert, the immune functions of DCs. RSV infection of DCs could alter their function and this could explain why protection after natural RSV infection is incomplete and of short duration. In this study, this interaction between DCs and RSV was investigated using a human primary culture model. DCs were generated from purified healthy adult volunteer peripheral blood monocytes. Effects of RSV upon DC phenotype with RSV primed DCs was measured using flow cytometry. Changes to viability and proliferation of cocultured DCs and T-cells were determined using microscopy with fluorescent dyes (Hoechst 33342 and propidium iodide). DC maturation was not prevented by the RSV challenge. RSV infected a fraction of DCs (10-30%) but the virus replicated slowly in these cells with only small reduction to cell viability. DCs challenged with RSV stimulated T-cell proliferation less well than lipopolysaccharide. This is the first study to demonstrate RSV infection of human monocyte derived DCs and suggests that the virus does not significantly interfere with the function of these cells and potentially may promote cellular rather than humoral responses.
Adult↗
Anticholinergic drugs for wheeze in children under the age of two years.
BACKGROUND: Wheeze in infancy and early childhood is common and appears to be increasing though the magnitude of any increase is unclear. Most wheezing episodes in infancy are precipitated by respiratory viral infections. Treatment of very young children with wheeze remains controversial. Anti-cholinergics are often prescribed but practice varies widely and the efficacy of this form of therapy remains the subject for debate. OBJECTIVES: Wheeze in infancy and early childhood is common and appears to be increasing. Most wheezing episodes in infancy are a result of viral infection. Bronchodilator medications such as beta2-agonists and anti-cholinergic agents are often used to relieve symptoms, but patterns of use vary. The objective of this review was to assess the effects of anti-cholinergic therapy in the treatment of wheezing infants. This is a second update of this review. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register of trials and the reference lists of articles. We contacted researchers in the field and industry sources. Searches were current as of June 2004. SELECTION CRITERIA: Randomised trials that compared anti-cholinergic therapy with placebo or beta2-agonists in wheezing children under two years of age. Children with acute bronchiolitis and chronic lung disease were excluded. DATA COLLECTION AND ANALYSIS: Eligibility for inclusion and quality of trials were assessed independently by two reviewers. MAIN RESULTS: Six trials involving 321 infants in three different settings were included. Compared with beta2-agonist alone, the combination of ipratropium bromide and beta2-agonist was associated with a reduced need for additional treatment, but no difference was seen in treatment response, respiratory rate or oxygen saturation improvement in the emergency department. There was no significant difference in length of hospital stay between ipratropium bromide and placebo; or between ipratropium bromide and beta2-agonist combined compared with beta2-agonist alone. However, combined ipratropium bromide and beta2-agonist compared to placebo showed significantly improved clinical scores at 24 hours. Parents preferred ipratropium bromide over nebulised water or placebo for relief of their children's symptoms at home. A further updated search conducted in June 2004 did not yield any new studies. AUTHORS' CONCLUSIONS: There is not enough evidence to support the uncritical use of anti-cholinergic therapy for wheezing infants, although parents using it at home were able to identify benefits.
Adrenergic Antagonists↗
A pilot study of oral L-arginine in cystic fibrosis.
Exhaled nitric oxide has previously been found to be low in cystic fibrosis. The aim of this study was to determine whether exhaled nitric oxide levels would increase in response to oral L-arginine supplementation administered daily for 4 weeks. Exhaled and nasal nitric oxide was measured weekly. Plasma L-arginine levels increased in response to supplementation but this was not reflected in an increase in eNO levels.
Administration, Oral↗
Respiratory syncytial virus and neutrophil activation.
Respiratory syncytial virus infects almost all children by 2 years of age. Neutrophils are the predominant airway leucocytes in RSV bronchiolitis and they are activated in the presence of infection. However it is not clear whether RSV can directly signal to activate neutrophil cytotoxic function. To investigate this we have used a preparation of RSV washed using a new centrifugal diafiltration method to rapidly remove inflammatory molecules produced by the epithelial cells used to propagate the RSV stock. Human neutrophils were isolated from peripheral blood and activated with either the unwashed crude RSV preparations or the purified intact RSV. Neutrophils were also challenged with purified RSV G-glycoprotein. The effect of challenging human neutrophils with these preparations of intact RSV, or the RSV G-glycoprotein, was assessed by measuring the cell surface expression of CD11b and CD18b, the phagocytic oxidative burst, and intracellular release of calcium pools. Neutrophils challenged with the washed RSV exhibited significantly lower activation of surface marker expression (P < 0.001) and oxidative burst (P < 0.001) than those challenged with unwashed virus or with virus free supernatant. There was no increase in intracellular calcium release on exposure to the washed RSV. Purified G glycoprotein did not stimulate neutrophils, whilst the use of a blocking antibody to the F protein did not prevent unwashed RSV from activating cytotoxic responses. These results suggest that neutrophils have no innate signalling system that recognizes RSV but they are activated at sites of RSV infection as a result of the cytokines and inflammatory molecules released by virally infected cells.
Antibodies, Viral↗
Ethical aspects of using radiolabelling in aerosol research.
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Aerosols↗
Omega-3 fatty acids (from fish oils) for cystic fibrosis.
BACKGROUND: Epidemiological (population studies) and other studies suggest that a diet rich in omega-3 essential fatty acids (derived from fish oil) may have beneficial anti-inflammatory effects for chronic conditions such as cystic fibrosis. OBJECTIVES: To determine whether there is evidence that omega-3 polyunsaturated fatty acid supplementation reduces morbidity and mortality. To identify any adverse events associated with omega-3 polyunsaturated fatty acid supplementation. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group specialised trials register, which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Authors and persons interested in the question were contacted. Date of the most recent search of the Group's specialised register: May 2002. SELECTION CRITERIA: Randomised controlled trials in patients with cystic fibrosis in which omega-3 fatty acid supplements were compared with a placebo oil. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected the trials to be included in the review and assessed the methodological quality of the trials using two approaches: Cochrane assessment of allocation concealment and Jadad quality assessment score. Using data acquisition forms, two reviewers independently extracted data. Missing data has been requested. MAIN RESULTS: The initial literature search identified six trials. Two trials, involving 31 participants satisfied our inclusion criteria and were included in the review. Both compared omega-3 fatty acids to olive oil controls for a six week treatment period. One study (19 participants) showed an improvement in FEV1, FVC, Shwachman score and reduction in sputum volume in the fish oil group at the end of this short treatment period. REVIEWER'S CONCLUSIONS: The review of trials found that regular omega-3 supplements may provide some benefits for people with cystic fibrosis with relatively few adverse effects, although the evidence is insufficient to draw firm conclusions. There is insufficient evidence to recommend routine use of supplements of omega-3 fatty acids in people with cystic fibrosis. The most notable feature highlighted by this review was the lack of data for many of the outcomes likely to be meaningful to people with or making treatment decisions about CF. A large, long-term, multi-centre, randomised controlled study is needed in order to determine if there is a significant therapeutic effect and to assess the influence of disease severity, dosage and duration of treatment. Future researchers should note the need for additional pancreatic enzymes.
Cystic Fibrosis↗
Budesonide/formoterol in a single inhaler versus inhaled corticosteroids alone in the treatment of asthma.
The aim of this study was to evaluate the efficacy (expressed as effect on lung function) and tolerability of Symbicort (budesonide/formoterol in a single inhaler) in children with asthma. This was a double-blind, double-dummy, randomized, parallel-group, multicenter trial. After a 2-4-week run-in period, 286 asthmatic children (177 boys, 109 girls; mean age, 11 years; mean forced expiratory volume in 1 sec (FEV(1)), 75% predicted normal), previously treated with inhaled corticosteroids (average dose 548 microg/day), were randomized to 12 weeks' treatment with either budesonide/formoterol 80/4.5 microg, two inhalations twice daily (n = 148), or an equivalent dose of budesonide 100 microg, two inhalations twice daily (n = 138). Efficacy variables included morning and evening peak expiratory flow (PEF), spirometery, asthma symptoms, and use of rescue medication (beta(2)-agonists). Serial FEV(1) assessments were carried out on a subgroup of children (budesonide/formoterol, n = 41; budesonide, n = 40) at randomization and at week 12. Relative to baseline, morning PEF (primary variable) increased to a significantly greater extent with budesonide/formoterol than with budesonide alone (7.22% predicted normal vs 3.45% predicted normal; P < 0.001). Evening PEF also increased significantly with budesonide/formoterol (6.13% predicted normal vs. 2.73% predicted normal; P < 0.001), as did mean FEV(1) and serial FEV(1) measured over 12 hr (both P < 0.05). Similar improvements in asthma symptoms and rescue medication use were observed in both groups. The two treatment groups were similar in terms of their adverse-event profile and rates of discontinuation. Budesonide/formoterol in a single inhaler provided rapid improvements in PEF and FEV(1) compared to inhaled budesonide alone. These improvements were sustained throughout the study period. Budesonide/formoterol was well-tolerated in children with moderate persistent asthma.
Administration, Inhalation↗
Differential response of wheezes and ruttles to anticholinergics.
Computerised breath sounds analysis was used to assess the response of infants with wheeze and ruttles to the drug ipratropium bromide. A mean decrease in breath sounds intensity occurred in infants with ruttles after five minutes (20.5 dB), but not until 20 minutes in those with wheeze (8.1 dB). This differential response may be related to different underlying pathophysiology.
Bronchodilator Agents↗
Colistin stimulates the activity of neutrophil elastase and Pseudomonas aeruginosa elastase.
Nonantimicrobial effects of antibiotics may contribute to their activity in the treatment of infective airway disease. The aim of this study was to identify antibiotics used for the treatment of infection in cystic fibrosis that may alter the activity of human neutrophil elastase (HNE) and Pseudomonas aeruginosa elastase (PE). The effect of antibiotics on the activity of purified HNE and PE, and HNE in sputum was assessed using colourimetric and fluorescent substrate assays by kinetic measurements, and by examining the interaction of HNE with inhibitors. Ceftazidime, tobramycin, and gentamycin slightly inhibited purified HNE activity whereas erythromycin and colistin significantly stimulated purified HNE and PE (395 and 557%, respectively). However, only colistin increased HNE activity in sputum (+102%) and was therefore studied in more detail. This increase in activity was not due an interference with the specific inhibition of HNE by alpha1-antitrypsin but colistin was found to reverse the inhibitory effects of small molecular weight molecules like heparin. Colistin increases the activity of human neutrophil elastase and Pseudomonas aeruginosa elastase, two proteases that contribute to the pathogenesis of cystic fibrosis airway disease.
Adolescent↗
Neutrophil survival is prolonged in the airways of healthy infants and infants with RSV bronchiolitis.
Large numbers of neutrophils in the airway of infants infected by respiratory syncytial virus (RSV) are recruited by chemokines, such as interleukin-8, and specific inflammatory molecules can delay apoptosis increasing their longevity. The aim of this study was to investigate whether airway secretions in RSV bronchiolitis contain factors that influence neutrophil apoptosis. Nasal lavage fluid (NLF) was obtained from 24 infants with RSV bronchiolitis (31 infant controls and 12 adults). Neutrophils isolated from healthy adult volunteers were incubated with the NLF in Dulbecco modified Eagle medium (DMEM) for 24 h, and apoptosis and necrosis were quantified using Hoechst 33342 and propidium iodide viability dyes. The presence of putative factors that delay neutrophil apoptosis was investigated using inhibitors to leukotriene-B4, lipopolysaccharide and the IL-8 receptor CXCR2, and blocking antibodies to granulocyte-monocyte colony-stimulating factor. Characterisation of NLF involved tests of thermal instability, proteolysis, deoxyribonuclease digestion and molecular filtration. NLF from infants with RSV bronchiolitis and controls significantly delayed neutrophil apoptosis, whereas NLF from healthy adults did not. None of these inhibitor molecules blocked this delay in apoptosis but activity was heat liable and >3 kDa. The study showed that nasal lavage fluid from infants significantly delays neutrophil apoptosis. The speculation is that the prolonged survival of neutrophils in the infant airway contributes to the characteristic accumulation of neutrophils in the airways of infants with respiratory infections.
Adult↗
The effect of ribavirin to treat previously healthy infants admitted with acute bronchiolitis on acute and chronic respiratory morbidity.
The role of ribavirin in the treatment of acute bronchiolitis is controversial. It has been suggested that the use of ribavirin may be of benefit during the acute illness and may reduce subsequent recurrent respiratory morbidity. This randomized, double-blind, placebo-controlled study was designed to determine whether ribavirin administered during the acute illness would have an influence on respiratory morbidity during both the acute illness and during the following year. Bronchial reactivity 6 months after the acute illness was also assessed. Forty previously well infants with moderately severe acute bronchiolitis were recruited during three winter epidemics. Subjects received study medication for 18 h a day. Management was otherwise unaltered. Subjects were evaluated daily by the investigator and subsequently assessed at 6 weeks, 6 months and 1 year following the acute illness. Assessment of bronchial hyper-responsiveness was assessed at 6 months of age using total body plethysmography and an established ultra-sonically nebulized distilled water challenge. A total of 40 patients (21 ribavirin, 19 placebo) were entered into the study. The two groups did not differ with respect to age, gender or clinical severity on entry to the trial. No significant differences were identified in the rate of clinical improvement over the first 24 h, the time to discharge, bronchial responsiveness at 6 months of age, frequency of significant respiratory symptoms over the first year of life and the frequency of prescribed bronchodilators and inhaled steroids during the year of follow-up. This study was unable to demonstrate any clinical benefit from the use of ribavirin in the acute illness or during subsequent follow-up for 1 year.
Antiviral Agents↗
Guidelines for devices and choices.
Asthma patients can be treated safely and effectively with the compounds and inhalation devices currently available. However, the choice of devices is so wide that the healthcare professional may be easily confused, and the effectiveness of treatment reduced. Clear guidelines are needed to help resolve this difficulty; however, those currently available do not contain enough useful information on the different delivery systems to assist the selection process. The function of the anti-asthma drug (i.e., preventer or reliever) should determine the choice of device. For inhaled corticosteroids, the device should provide effective and reliable delivery, while simplicity in use will aid good inhalation technique. A device that minimizes systemic absorption of these drugs will improve drug safety. The devices of choice are pressurized metered dose-inhalers (pMDIs) with spacers and some dry powder inhalers (DPIs). The main selection criteria for short-acting beta2-agonists are portability and patient acceptability. DPIs and pMDIs are the most suitable systems for these drugs. Cost is an important consideration for both drug types.
Administration, Inhalation↗
Survey of respiratory sounds in infants.
BACKGROUND: Over the last decade there has been an apparent increase in childhood wheeze. We speculated that much of the reported increase may be attributed to the term wheeze being adopted by parents to describe a variety of other forms of noisy breathing. AIMS: To investigate terminology used by parents to describe their children's breath sounds. METHODS: An interview was carried out with the parents of 92 infants with noisy breathing, beginning with an open question and then directed towards a more detailed description. Finally, the parents were asked to choose from a wheeze, ruttle, and stridor on imitation by the investigator and video clips of children. RESULTS: Wheeze was the most commonly chosen word on initial questioning (59%). Only 36% were still using this term at the end of the interview, representing a decrease of one third, whereas the use of the word ruttles doubled. CONCLUSIONS: Our results reflect the degree of inaccuracy involved in the use of the term wheeze in clinical practice, which may be leading to over diagnosis. Imprecise use of this term has potentially important implications for therapy and clinical trials.
Communication↗
Exhaled nitric oxide is reduced in infants with cystic fibrosis.
BACKGROUND: Exhaled nitric oxide levels are low in patients with cystic fibrosis (CF), despite the chronic inflammation present in the airways. This study aimed to determine whether levels of exhaled nitric oxide were reduced prior to the onset of respiratory symptoms in infants with CF. METHODS: The levels of exhaled nitric oxide were measured using a chemiluminescence analyser in five infants with CF and 11 healthy control subjects, both groups having a mean age of 48.6 days. RESULTS: Mean levels of exhaled nitric oxide were significantly lower in infants with CF than in the control group (4.9 ppb v 12.1 ppb; p=0.01). CONCLUSIONS: This finding may be the key to understanding the inflammatory processes in early cystic fibrosis and may lead to novel treatment approaches.
Breath Tests↗
Anti-cholinergic drugs for wheeze in children under the age of two years.
BACKGROUND: Wheeze in infancy and early childhood is common and appears to be increasing though the magnitude of any increase is unclear. Most wheezing episodes in infancy are precipitated by respiratory viral infections. Treatment of very young children with wheeze remains controversial. Anti-cholinergics are often prescribed but practice varies widely and the efficacy of this form of therapy remains the subject for debate. OBJECTIVES: Wheeze in infancy and early childhood is common and appears to be increasing. Most wheezing episodes in infancy are a result of viral infection. Bronchodilator medications such as beta2-agonists and anti-cholinergic agents are often used to relieve symptoms, but patterns of use vary. The objective of this review was to assess the effects of anti-cholinergic therapy in the treatment of wheezing infants. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register and the reference lists of articles. We contacted researchers in the field and industry sources. SELECTION CRITERIA: Randomised trials that compared anti-cholinergic therapy with placebo or beta2-agonists in wheezing children under two years of age. Children with acute bronchiolitis and chronic lung disease were excluded. DATA COLLECTION AND ANALYSIS: Eligibility for inclusion and quality of trials were assessed independently by two reviewers. MAIN RESULTS: Six trials involving 321 infants in three different settings were included. Compared with beta2-agonist alone, the combination of ipratropium bromide and beta2-agonist was associated with a reduced need for additional treatment, but no difference was seen in treatment response, respiratory rate or oxygen saturation improvement in the emergency department. There was no significant difference in length of hospital stay between ipratropium bromide and placebo; or between ipratropium bromide and beta2-agonist combined compared with beta2-agonist alone. However, combined ipratropium bromide and beta2-agonist compared to placebo showed significantly improved clinical scores at 24 hours. Parents preferred ipratropium bromide over nebulised water or placebo for relief of their children's symptoms at home. REVIEWER'S CONCLUSIONS: There is not enough evidence to support the uncritical use of anti-cholinergic therapy for wheezing infants, although parents using it at home were able to identify benefits.
Asthma↗
When a "wheeze" is not a wheeze: acoustic analysis of breath sounds in infants.
Epidemiological studies indicate that the prevalence of "wheeze" is very high in early childhood. However, it is clear that parents and clinicians frequently use the term "wheeze" for a range of audible respiratory noises. The commonest audible sounds originating from the lower airways in infancy are ruttles, which differ from classical wheeze in that the sound is much lower in pitch, with a continuous rattling quality and lacking any musical features. The aim of this study was to clearly differentiate wheeze and ruttles objectively using acoustic analysis. Lung sounds were recorded in 15 infants, seven with wheeze and eight with ruttles, using a small sensitive piezoelectric accelerometer, and information relating to the respiratory cycle was obtained using inductive plethysmography. The acoustic signals were analysed using a fast fourier transformation technique (Respiratory Acoustics Laboratory Environment programme). The acoustic properties of the two noises were shown to be quite distinct, the classical wheeze being characterized by a sinusoidal waveform with one or more distinct peaks in the power spectrum display; the ruttle is represented by an irregular nonsinusoidal waveform with diffuse peaks in the power spectrum and with increased sound intensity at a frequency of <600 Hz. It is important for clinicians and epidemiologists to recognize that there are distinct types of audible respiratory noise in early life with characteristic acoustic properties.
Fourier Analysis↗
Trying to deliver aerosols to upset children is a thankless task.
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Administration, Inhalation↗