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

Fungal pathogens are increasingly important causes of respiratory disease, yet the number of antifungal agents available for clinical use is limited. Use of amphotericin B deoxycholate is hampered by severe toxicity. Triazole agents currently available have significant drug interactions; fluconazole has a limited spectrum of activity and itraconazole was, until recently, available only in oral formulations with limited bioavailability. The development of resistance to all three agents is increasingly being recognized and some filamentous fungi are resistant to the action of all of these agents. In the past few years, new antifungal agents and new formulations of existing agents have become available.The use of liposomal amphotericin B preparations is associated with reduced, but still substantial, rates of nephrotoxicity and infusion-related reactions. An intravenous formulation of itraconazole has been introduced, and several new triazole agents have been developed, with the view of identifying agents that have enhanced potency, broader spectra of action and improved pharmacodynamic properties. One of these, voriconazole, has completed large-scale clinical trials. In addition, caspofungin, the first of a new class of agents, the echinocandins, which inhibit cell wall glucan synthesis, was approved for use in the US in 2001 as salvage therapy for invasive aspergillosis. It is hoped that the availability of these agents will have a significant impact on the morbidity and mortality of fungal respiratory infections. However, at the present time, our ability to assess their impact is limited by the problematic nature of conducting trials for antifungal therapy.

Patients with community-acquired pneumonia (CAP) are treated in hospital or in the ambulatory care setting depending on the severity of illness. Despite numerous guidelines proposed, there is no agreement on specific criteria for hospitalization other than the clinicians' experience. The purpose of this review is to discuss the importance of the appropriate choice and timely administration of antibacterial agents, either in the hospital or in the outpatient setting. Since a high proportion of CAP patients will not have an etiologic agent identified at the time of initiation of treatment, the choice of antibacterial therapy is usually empiric. Antibacterial agents with activity against pneumococci and atypical pathogens causing pneumonia are the preferred choices. Macrolides, doxycycline, or respiratory fluoroquinolones have been recommended by various guidelines committees in North America for the treatment of pneumonia in patients with or without underlying comorbidities. Because of the increasing resistance to beta-lactams as well other antibacterial agents such as macrolides, doxycycline, and sulfamethoxazole/trimethoprim (cotrimoxazole), it is important that clinicians are aware of local statistics on resistance to Streptococcus pneumoniae, as infection with this bacterium is associated with high rates of morbidity and mortality. More recently, fluoroquinolone resistance has been reported, but the percentage of pneumococcal strains resistant to this agent is relatively low compared with the other antibacterial agents. Switch (intravenous to oral) therapy is recommended for hospitalized patients with CAP to facilitate early discharge, which has been shown to improve patient satisfaction and reduce hospital costs. Early conversion to oral therapy has not been shown to be associated with increased complications or higher mortality. Following prompt intravenous therapy and stabilization, patients with CAP should be treated with oral therapy in the ambulatory setting.

Chlamydia pneumoniae is an intracellular pathogen that has been suggested to play a role in the pathology of asthma. However, so far none of the studies have provided clear evidence for a causative role of C. pneumoniae infections in asthma, although there is little doubt that chronic C. pneumoniae infection does aggravate asthma and should be treated. The diagnosis of C. pneumoniae infection is still a matter of concern for it is dependent on trained skilled personnel and can vary significantly between different diagnostic laboratories. This fact is also one of the major problems encountered when comparing epidemiological studies investigating the possible role of C. pneumoniae infections and their impact on the pathogenesis of other diseases. With regard to therapy, long-term treatment with macrolides is the best available method to eradicate C. pneumoniae. Successful therapy for C. pneumoniae, however, can also be complicated by the high possibility of de novo infection as epidemiological studies have shown that the prevalence of antibodies to C. pneumoniae increases with age in all populations studied. In the northern hemisphere the prevalence of C. pneumoniae is also affected by seasonal conditions. It is too early to draw any conclusions from the equatorial belt countries. The available data on C. pneumoniae in tropical countries indicate a much faster infection rate during early adulthood with 100% serological prevalence at an age greater than 25 years. This data, if confirmed, would argue against C. pneumoniae causing asthma since the asthma prevalence in those countries does not increase in a parallel pattern. An alternative interpretation of most studies could be that the increased rate of C. pneumoniae infections in patients with asthma results from a modified susceptibility towards the microorganism, due to yet unknown changes of the host cell's physiology. It should be kept in mind that increased prevalence of C. pneumoniae infection is not restricted to asthma. Further studies are needed to understand the role of C. pneumoniae, especially of chronic infection, in the pathogenesis of inflammatory diseases with a specific focus on the effect that the microorganism triggers in the infected host cell. Only when we understand what C. pneumoniae does to its host cell will we be able to judge its impact on the overall status of an affected patient, and this knowledge will help us to develop a successful therapy.

Directly Observed Therapy Shortcourse (DOTS) is composed of five distinct elements: political commitment; microscopy services; drug supplies; surveillance and monitoring systems and use of highly efficacious regimens; and direct observation of treatment. The difference in the way the term 'DOTS' as defined by WHO and interpreted by many observers has led to some misunderstanding. WHO generally uses the term to mean the five components of DOTS. But the word 'DOTS' is an acronym for Directly Observed Therapy Shortcourse. Many workers therefore interpret DOTS purely as direct supervision of therapy. DOTS is not an end in itself but a means to an end. In fact it has two purposes, to ensure that the patient with tuberculosis (TB) completes therapy to cure and to prevent drug resistance from developing in the community. The main criticism of DOTS rightly derives from the fact that some properly conducted randomized, controlled trials of directly observed therapy with or without the other components have shown no benefit from it. The problem is that it is impossible to design a study of modern directly observed therapy against the previous self-administered, poorly-resourced programs. As soon as a study is implemented, the attention to patients in the control (non-directly observed therapy) arm inevitably improves from the previous non-trial service situation. What is of concern is that in some trials less than 70% cure rates were achieved even in the direct observation arm. With no new drugs or adjuvant treatment available to bring the length of treatment down to substantially less than 6 months, DOTS offers the best means we have at our disposal for TB control.

There exists a complex, dynamic interaction between mechanical ventilation and the splanchnic vasculature that contributes to a myriad of gastrointestinal tract complications that arise during critical illness. Positive pressure-induced splanchnic hypoperfusion appears to play a pivotal role in the pathogenesis of these complications, the most prevalent of which are stress-related mucosal damage, gastrointestinal hypomotility and diarrhea. Furthermore, characteristics of the splanchnic vasculature make the gastrointestinal tract vulnerable to adverse effects related to positive pressure ventilation. While most of these complications seen in mechanically ventilated patients are reflections of altered gastrointestinal physiology, some may be attributed to medical interventions instituted to treat critical illness. Since maintenance of normal hemodynamics cannot always be achieved, pharmacologic prophylactic therapy has become a mainstay in the prevention of gastrointestinal complications in the intensive care unit. Improved understanding of the systemic effects of mechanical ventilation and greater application of lung-protective ventilatory strategies may potentially minimize positive pressure-induced reductions in splanchnic perfusion, systemic cytokine release and, consequently, reduce the incidence of gastrointestinal complications associated with mechanical ventilation. Herein, we discuss the pathophysiology of gastrointestinal complications associated with mechanical ventilation, summarize the most prevalent complications and focus on preventive strategies and available treatment options for these complications. The most common causes of gastrointestinal hemorrhage in mechanically ventilated patients are bleeding from stress-related mucosal damage and erosive esophagitis. In general, histamine H(2) receptor antagonists and proton pump inhibitors prevent stress-related mucosal disease by raising the gastric fluid pH. Proton pump inhibitors tend to provide more consistent pH control than histamine H(2) receptor antagonists. There is no consensus on the drug of choice for stress ulcer prophylaxis with several meta-analyses providing conflicting results on the superiority of any medication. Prevention of erosive esophagitis include careful use of nasogastric tubes and institution of strategies that improve gastric emptying. Many mechanically ventilated patients have gastrointestinal hypomotility and diarrhea. Treatment options for gastrointestinal motility are limited, thus, preventive measures such as correction of electrolyte abnormalities and avoidance of medications that impair gastrointestinal motility are crucial. Treatment of diarrhea depends on the underlying cause. When associated with Clostridium difficile infection antibacterial therapy should be discontinued, if possible, and treatment with oral metronidazole should be initiated.More studies are warranted to better understand the systemic effects of mechanical ventilation on the

Objective: To examine the relationship between changes in quality of life and measures of lung function and bronchial hyper-responsiveness (BHR) during treatment with high-dose inhaled corticosteroids in patients with uncontrolled asthma.

Methods: Thirty patients with uncontrolled asthma currently receiving inhaled corticosteroids (median dose 550 microg/day) were treated with beclomethasone dipropionate (BDP) dry powder 2000 microg/day for 4 weeks. Patients completed the Asthma Quality of Life Questionnaire (AQLQ), underwent bronchial challenge with methacholine and spirometry, and made entries in asthma diary cards at baseline and after treatment with beclomethasone dipropionate.

Results: The mean change in overall AQLQ score improved significantly (p < 0.05) during the 4-week period by 0.57 (95% CI 0.29-0.84, p < 0.05), representing a minimal important difference, with similar improvements in individual domains. Change in overall AQLQ score correlated significantly with FEV(1) (p < 0.001), forced mid-expiratory flow between 25-75% of vital capacity (FEF(25-75)) [p < 0.05] and morning PEF (p < 0.05), but not with methacholine PD(20) i.e. the provocative dose of methacholine causing a 20% fall in FEV(1).

Conclusions: Quality-of-life scores related to changes in lung function but not BHR during short-term high-dose inhaled corticosteroid therapy for uncontrolled asthma.

Asthma is a significant and increasing health problem. Airway inflammation and hyperresponsiveness are key pathophysiological mechanisms underlying asthma. Currently, effective treatments target these two processes and can lead to clinically important improvements in disease control. At present, decisions to initiate or modify therapy are based on symptoms and measures of airway caliber, with no direct assessment of airway inflammation or hyperresponsiveness. It is now possible to measure airway inflammation using noninvasive markers such as exhaled gases, induced sputum and serum measurements. Exhaled nitric oxide (eNO) and induced sputum eosinophils show the greatest promise as clinically useful markers of airway inflammation in asthma. Induced sputum can now be applied to the diagnosis of airway diseases, based on its ability to detect eosinophilic bronchitis in cough, and to differentiate between eosinophilic and non-eosinophilic asthma. The place of induced sputum and eNO in the ongoing monitoring of patients with asthma are now being investigated in controlled trials.

Management of recurrent malignant pleural effusion, a common complication of malignancy, poses a challenge to clinicians. Although almost one century has elapsed since the introduction of the pleurodesis procedure, the ideal approach and best agent are still to be defined. Optimally, pleurodesis should be done at the bedside with a minimally invasive procedure, and suitable agents to achieve pleural symphysis should be inexpensive, available worldwide and free of adverse effects. To date, no substance completely fulfills these requirements. Silver nitrate should be considered for pleurodesis because of its low cost and ease of handling. Although talc has been used most frequently to induce pleurodesis, reports of death due to acute respiratory failure have raised concerns about the safety of this agent. Tetracycline, an effective alternative used in the past, is no longer commercially available. This agent has been substituted with derivatives of tetracycline, such as minocycline and doxycycline with success rates similar to those with tetracycline. Several antineoplastic agents have been injected into the pleural space with the aim of producing pleural symphysis, the most representative of this group being bleomycin. Recent knowledge of the molecular mechanisms involved in pleural inflammation has brought into focus new substances, such as transforming growth factor beta and vascular endothelial growth factor, which may be used as pleurodesis agents in the future. Nevertheless, more studies are necessary to better define the potential of these substances in the induction of pleural symphysis.Ideally, a sclerosing agent should be cost-effective, available worldwide and easily administered. Talc will probably stand as the preferred agent to be used for pleurodesis in malignant pleural effusion because of its efficacy, easy manipulation and handling. However, further investigation is necessary to minimize adverse effects related to talc.

The intimate anatomical and physiologic relationship between the upper airway and esophagus consists of complex interactions between various muscles and nerves with both voluntary and involuntary patterns of control. Alterations in this harmonic relationship can lead to swallowing abnormalities ranging from dysphagia to gross aspiration, gastroesophageal reflux disease (GERD) and chronic cough. There is a paucity of data regarding pathologic alterations in the upper airway-esophageal relationship in patients with COPD. The association between GERD and respiratory symptoms is well recognized in the setting of asthma; however, the nature of this relationship remains controversial. The association of GERD and COPD is even less clear. A review of the limited data on GERD and swallowing abnormalities in patients with COPD indicate that prevalence of GERD and esophageal disorders in patients with COPD is higher than in the normal population. However, its contribution to respiratory symptoms, bronchodilator use and pulmonary function in patients with COPD remains unknown. Although dysphagia and swallowing dysfunction on videofluoroscopic swallow evaluation are common in patients with COPD, their role as exacerbators of COPD remains to be elucidated. Further clinical research is necessary to evaluate the role of GERD and swallowing dysfunction in both stable and acute exacerbation of COPD.

Occupational rhinitis is a common heterogeneous group of inflammatory conditions in the nose, caused by exposure to airborne irritants and sensitizers in the occupational environment. The mechanism can be allergic, neurogenic or toxic. Data from several epidemiologic studies indicate that animal dander, organic dusts, latex and chemicals can cause occupational rhinitis, but because of methodological problems as well as weaknesses in the definition of occupational rhinitis, occupational exposure is probably an underestimated cause of rhinitis. The effect of rhinitis on the mental aspects of quality of life and substantial costs due to loss of productivity make it important to diagnose and treat occupational rhinitis. Diagnosis relies on a history of exposure, skin prick testing and, if possible, nasal provoacation. Avoidance of exposure, protective measures at the workplace and medical treatment, with agents such as second generation antihistamines and nasal corticosteroids, can make it possible to avoid progress of the disease from rhinitis to asthma. The efficacies of montelukast, a leukotrienne receptor antagonist, and omalizumab, an anti-immunoglobulin E monoclonal antibody in the treatment of occupational rhinitis are yet to be evaluated