American journal of respiratory medicine : drugs, devices, and other interventions最新文献

Obstructive sleep apnea (OSA) is a common condition of childhood, and is associated with significant morbidity. Prevalence of the condition peaks during early childhood, due in part to adenoidal and tonsillar enlargement within a small pharyngeal space. The lymphoid tissues regress after 10 years of age, in the context of ongoing bony growth, and there is an associated fall in the prevalence of OSA. Obstruction of the nasopharynx by adenoidal enlargement promotes pharyngeal airway collapse during sleep, and the presence of large tonsils contributes to airway obstruction. Administration of systemic corticosteroids leads to a reduction in the size of lymphoid tissues due to anti-inflammatory and lympholytic effects. However, a short course of systemic prednisone has been demonstrated not to have a significant effect on adenoidal size or the severity of OSA, and adverse effects preclude the long-term use of this therapy. Intranasal corticosteroids are effective in relieving nasal obstruction in allergic rhinitis, and allergic sensitization is more prevalent among children who snore than among those who do not snore. Intranasal corticosteroids have also been demonstrated to reduce adenoidal size, independent of the individual's atopic status. There is preliminary evidence of an improvement in the severity of OSA in children treated with intranasal corticosteroids, but further studies are needed before such therapy can be routinely recommended. Prescribing clinicians should take into account the potential benefits to the patient, the age of the child, the presence of comorbidities such as allergic rhinitis, the agent used, and the dose and duration of treatment when considering such therapy.

The prevalence of nontuberculous mycobacteria (NTM) recovered from patients with cystic fibrosis (CF) appears to be increasing, probably related to improved surveillance and microbiological procedures and an increase in the life expectancy of patients with CF. The distinction between active lung infection and colonization is often difficult to assess in patients with CF because of the marked overlap in the clinical and radiological presentation of CF lung disease and lung disease caused by NTM infection. The possibility of active NTM lung infection should be considered in those patients with compatible radiographic changes and/or progressive deterioration in lung function who do not improve with specific antibiotic therapy and who have repeatedly positive sputum cultures and smears for NTM. Patients with repeatedly positive results of acid-fast smears are more likely to be infected than colonized. Pseudomonas overgrowth may confuse the results of sputum and bronchoalveolar lavage fluid cultures. Decontamination of respiratory samples from patients with CF with 5% oxalic acid results in improved bacteriological recovery of NTM. Skin tests are of limited value as a screening tool for NTM. Since the course of NTM lung infection is often slow, careful follow-up with repeated sputum cultures, chest radiographs and computed tomography (CT) scans may be needed. Treatment of NTM lung disease in patients with CF presents great difficulties because of abnormal gastrointestinal drug absorption and pharmacokinetics in this patient population. Treatment varies according to the mycobacterial species isolated. Long-term multidrug regimens including rifampin (rifampicin) and ethambutol are usually required. Monitoring serum drug levels is a useful indicator of correct dosage in order to prevent adverse effects due to potential drug interactions and altered pharmacokinetics in patients with CF.

The future management of patients with allergic asthma is poised to change in the coming one to two decades. This prediction is based on fundamental new insights into the pathogenesis of disease, gained through the study of both humans and experimental models of asthma. These studies have revealed that allergic asthma is an immune-mediated disease which, despite the redundancy characteristic of all immune responses, may be induced through a single dominant signaling cascade called the interleukin (IL)-4/IL-13 signaling pathway. In addition to the cytokine IL-4, this pathway includes IL-13, the cytokine receptor subunit IL-4 receptor alpha (IL-4Ralpha), Janus-associated tyrosine kinases and the transcription factor, signal transducer and activator of transcription 6. The IL-4 signaling pathway controls the most important cellular developmental (afferent) events that underlie asthma. These include T helper (Th) type 2 cell activation, B cell activation and immunoglobulin (Ig) E secretion, mast cell development, and effector (efferent) events related exclusively to immune effects on the lung such as goblet cell metaplasia and airway hyperresponsiveness. Any of the IL-4 signaling molecules are potentially amenable to pharmacological intervention, but a detailed understanding of the entire pathway is required to appreciate their actual potential for drug development. For example, neutralization strategies that target only IL-4 are unlikely to succeed because they leave IL-13 free to continue the signaling cascade. In contrast, neutralization of IL-4Ralpha may represent a more feasible strategy, as it should prevent signaling by both IL-4 and IL-13. The therapeutic potential of targeting intracytoplasmic tyrosine kinases has already been achieved with the use of small molecules, suggesting that this approach may be realistically adopted for the treatment of asthma. However, well designed asthma clinical trials are warranted to determine with certainty, the efficacy of therapies based on IL-4/IL-13 blockade.

Neutrophils have been implicated in the pathogenesis of many inflammatory lung diseases, including the acute respiratory distress syndrome, chronic obstructive pulmonary disease and asthma. The CXC chemokine interleukin (IL)-8, is a potent neutrophil recruiting and activating factor and the detection of IL-8 in clinical samples from patients with these diseases has led clinicians to believe that antagonism of IL-8 may be a practicable therapeutic strategy for disease management. Work over the last decade has concentrated on both the molecular mechanisms by which IL-8 is produced in the inflammatory setting and also on the manner in which IL-8 activates the neutrophil. Expression of the IL-8 gene appears to be controlled by several components of the inflammatory milieu. Whilst lipopolysaccharide, IL-1beta and tumor necrosis factor-alpha are capable of augmenting IL-8 production, IL-10 is a potent inhibitor of IL-8 synthesis and appears to play an auto-regulatory role. Regulation of the IL-8 gene is under the control of nuclear factor kappaB which appears to be a primary target for corticosteroid-mediated repression of IL-8 production. IL-8 exerts is effects on neutrophils by binding with high affinity to two receptors on its cell surface, the chemokine receptors CXCR1 and CXCR2. These closely related receptors belong to the superfamily of G-protein coupled receptors, proteins that historically have proved amenable to antagonism by small molecules. The recent descriptions in the literature of highly potent small molecule antagonists of CXCR2 and their success in blocking in vivo trafficking of neutrophils suggest that antagonism of IL-8 at the receptor level is a viable therapeutic strategy. Clinical trials of such compounds will ultimately provide crucial information currently lacking and will define whether or not IL-8 blockade provides future therapy in pulmonary disease.

Objective: The purpose of this study was to examine pulmonary function tests in children at various time points in their recovery from empyema.

Design: Cross-sectional study.

Setting: Academic Children's Hospital.

Patients: Pediatric patients with a diagnosis of empyema between 1992-2000.

Results: A total of 45 pulmonary function tests were carried out in 36 study participants. Within 3 months of hospital discharge, 91% of pulmonary function tests demonstrated a restrictive pattern with a mean forced vital capacity (FVC) of 69.2 +/- 4% and a mean total lung capacity (TLC) of 74.9 +/- 4% of predicted. The incidence of restriction in pulmonary function significantly decreased over time and for patients tested > 1 year from hospital discharge the mean FVC was 87.1 +/- 2% and the mean TLC 95.0 +/- 2% of predicted. However, 19% of the patients tested > 1 year from discharge demonstrated a mild restrictive pattern and 16% demonstrated a mild obstructive changes. Patients with abnormal lung function > 1 year from hospital discharge did not demonstrate any signs or symptoms of respiratory insufficiency .

Conclusion: There is a high incidence of restrictive patterns in lung function for children tested within 3 months from hospital discharge for empyema. The incidence of restrictive patterns decreased significantly over time and most patients tested >1 year from hospital discharge demonstrated normal lung function.

The administration of systemic corticosteroids for patients with exacerbations of chronic obstructive pulmonary disease (COPD) has become common practice over the past 25 years. This practice remained somewhat controversial because corticosteroids can have serious adverse effects and initial clinical trials provided inconclusive evidence concerning their efficacy. Results from recent clinical trials indicate that systemic corticosteroids are modestly effective in shortening the duration of severe exacerbations of COPD. Systemic corticosteroids administered intravenously or orally to hospitalized patients with exacerbations of COPD reduced the absolute treatment failure rate by about 10%, increased the forced expiratory volume in 1 second (FEV1) by about 100 ml, and shortened the hospital stay by 1 to 2 days. Oral corticosteroids probably confer similar benefits when used for treating moderately severe COPD exacerbations in an out-patient setting. The optimal starting dose of corticosteroids is not known, but the duration of treatment should not extend longer than 2 weeks. Hyperglycemia is the most common adverse event, but secondary infections, mental disturbances, and myopathies may also occur.

Chronic fatigue syndrome (CFS) is a recognized clinical illness of unknown cause and pathophysiologic mechanisms. Immunizing patients against influenza would seem to be a prudent strategy since infection has been associated with symptom exacerbation. However, patients with CFS have demonstrated variable abnormalities in the immune system, the clinical significance of which is unclear. Anecdotal information has suggested that, due to the etiologic uncertainty surrounding CFS, many patients reject immunization, fearful of untoward effects. This article attempts to clarify the situation by reviewing immunologic findings in CFS and influenza vaccines in current use. Results from a recent survey of perceptions of patients with CFS regarding immunization revealed that 31% felt immunization was neither safe nor beneficial. This opinion was universal in those patients who had never received influenza vaccine. Among patients who had received vaccine and experienced an adverse effect, 26% felt the vaccine was safe and 28% felt it was beneficial. Among those who had received vaccine without an adverse effect, 45% believed the vaccine was safe, and 55% felt it was effective. CFS patients as a group expressed concern that influenza vaccine would alter an already dysfunctional immune system, or worsen CFS symptoms. Significantly more patients with CFS who had never received influenza vaccine voiced this opinion than did patients who had received immunization for influenza in the past. Contrary to the opinions expressed by the sample, clinical trials in CFS have yet to find that any type of immunization has produced a deleterious effect on symptoms or functioning. Moreover, patients with CFS in a randomized, placebo-controlled, double-blind trial of influenza immunization produced an antibody titer in the protective range to inactivated trivalent influenza vaccine, although the geometric mean titer was slightly blunted compared with healthy vaccinees. Although patients with CFS in placebo and active groups reported four times the number of post-injection adverse effects of healthy vaccinees, data re-analysis revealed that this finding was related to the overlap of common, post-influenza immunization symptoms and CFS constitutional symptoms. CFS is a poorly understood illness and some patients may believe in causal theories that lead to the rejection of disease prevention strategies such as immunization. However, influenza immunization appears to provide protective antibody levels without worsening CFS symptoms or causing excessive adverse effects. Efforts to motivate patients with CFS to obtain annual influenza immunization should take into account illness perceptions and concentrate on education based on placebo-controlled trials.

Adenosine, an endogenous signaling nucleoside that modulates many physiological processes has been implicated in playing an ever increasingly important role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). All cells contain adenosine and adenine nucleotides and the cellular production of adenosine is greatly enhanced under conditions of local hypoxia as may occur in inflammatory conditions such as asthma and COPD. In 1983, it was first reported that inhaled adenosine causes dose-related bronchoconstriction in patients with both allergic and non-allergic asthma but not in healthy volunteers. This hyperresponsiveness was also reported in patients with COPD, with those patients who smoked exhibiting a significantly greater response. This bronchoconstrictor effect of adenosine is orchestrated through the stimulation of specific cell membrane receptors and involves an important inflammatory cell, the mast cell. There is substantial evidence which suggests that mast cell activation is central to this unique response to adenosine. Mast cell mediator release makes a significant contribution towards airflow obstruction and the consequent symptoms in patients with asthma. Over the last two decades, researchers have investigated the effect of mast cell inhibitors as well as mast cell mediator receptor antagonists and their role in attenuating the bronchoconstrictor response to inhaled adenosine 5'-monophosphate (AMP). Promising results have been shown using mast cell stabilizers, histamine H1 receptor antagonists, selective cysteinyl leukotriene-1 receptor antagonists and inhibitors of 5-lipoxygenase and cyclo-oxygenase. Through these findings, the mast cell has been recognized as being a critical inflammatory cell in the adenosine-induced response in patients with asthma and COPD. To date, four subtypes (A1, A2A, A2B, A3) of adenosine receptors have been cloned each with a unique pattern of tissue distribution and signal transduction. Activation of these receptors has pro- and anti-inflammatory consequences making the development of agonists and/or antagonists at these receptor sites a novel approach in the treatment of patients with asthma and COPD. This review highlights the importance of adenosine in the pathophysiology of asthma and COPD, the critical role of the mast cell and the potential to target the adenosine receptor subtype in patients with asthma and COPD. The complete characterization of these adenosine receptor subtypes in terms of their distribution in humans and the development of selective agonists and antagonists, holds the key to our complete understanding of the role of this important mediator in asthma and COPD.

Status asthmaticus is a life-threatening episode of asthma that is refractory to usual therapy. Recent studies report an increase in the severity and mortality associated with asthma. In the airways, inflammatory cell infiltration and activation and cytokine generation produce airway injury and edema, bronchoconstriction and mucus plugging. The key pathophysiological consequence of severe airflow obstruction is dynamic hyperinflation. The resulting hypoxemia, tachypnea together with increased metabolic demands on the muscles of respiration may lead to respiratory muscle failure. The management of status asthmaticus involves intensive pharmacological therapy particularly with beta-adrenoceptor agonists (beta-agonists) and corticosteroids. Albuterol (salbutamol) is the most commonly used beta2-selective inhaled bronchodilator in the US. Epinephrine (adrenaline) or terbutaline, administered subcutaneously, have not been shown to provide greater bronchodilatation compared with inhaled beta-agonists. Corticosteroids such as methylprednisolone should be administered early. Aerosolized corticosteroids are not recommended for patients with status asthmaticus. Inhaled anticholinergic agents may be useful in patients refractory to inhaled beta-agonists and corticosteroids. In patients requiring mechanical ventilation, the strategy aims to avoid dynamic hyperinflation by enhancing expiratory time to allow complete exhalation. Complications of dynamic inflation are hypotension and barotrauma. Sedation with opioids, benzodiazepines or propofol is required to facilitate ventilator synchrony but neuromuscular blockade should be avoided as myopathy has been a reported complication. Overall, in the management of patients with status asthmaticus, the challenge to the pulmonary/critical care clinician is to provide optimal pharmacological and ventilatory support and avoid the adverse consequences of dynamic hyperinflation.

Inhaled formoterol is a long-acting selective beta2-adrenoceptor agonist, with an onset of action of 5 minutes postdose and a bronchodilator effect that lasts for at least 12 hours. Statistically significant and clinically relevant (>120 ml) improvements in lung function [assessed using standardized/normalized area under the forced expiratory volume in 1 second (FEV1) versus time curve (AUC FEV1)] were observed with inhaled formoterol 12 microg twice daily (the approved dosage in the US) compared with placebo in 12-week and 12-month, randomized, double-blind trials in patients with chronic obstructive pulmonary disease (COPD). The bronchodilator efficacy of formoterol 12 microg twice daily was greater than that of oral slow-release theophylline (individualized dosages) in a 12-month trial or inhaled ipratropium bromide 40 microg four times daily in a 12-week trial. Improvement in AUC FEV1 with formoterol, but not theophylline, compared with placebo was observed in patients with irreversible or poorly-reversible airflow obstruction. Formoterol also significantly improved health-related quality of life compared with ipratropium bromide or placebo and significantly reduced symptoms compared with placebo. Combination therapy with formoterol 12 microg twice daily plus ipratropium bromide 40 microg four times daily was significantly more effective than albuterol (salbutamol) 200 microg four times daily plus the same dosage of ipratropium bromide in a 3-week, randomized, double-blind, double-dummy, crossover trial. Inhaled formoterol was well tolerated in clinical trials. The incidence of investigator-determined drug-related adverse events with inhaled formoterol 12 microg twice daily was similar to that with placebo and inhaled ipratropium bromide 40 microg four times daily but lower than that with oral slow-release theophylline (individualized dosages). Importantly, there were no significant differences between formoterol and placebo or comparator drugs in cardiovascular adverse events in patients with COPD and corrected QT interval values within the normal range. In conclusion, inhaled formoterol improved lung function and health-related quality of life and reduced symptoms relative to placebo in clinical trials in patients with COPD. The drug had greater bronchodilator efficacy than oral slow-release theophylline or inhaled ipratropium bromide and showed efficacy in combination with ipratropium bromide. The adverse events profile (including cardiovascular adverse events) with formoterol was similar to that with placebo. Thus, inhaled formoterol may be considered as a first-line option for the management of bronchoconstriction in patients with COPD who require regular bronchodilator therapy for the management of symptoms.