The adult respiratory distress syndrome (ARDS) is a form of acute lung injury that is characterized by florid extravascular fibrin deposition. Thrombosis in the pulmonary vasculature and disseminated intravascular coagulation have also been observed in association with ARDS. Fibrin deposition does not occur in the normal lung but is virtually universal in acute lung injury induced by disparate insults. A large body of basic and preclinical evidence further implicates abnormalities of pathways of fibrin turnover in the pathogenesis of acute inflammation and fibrotic repair. Coagulation is locally upregulated in the injured lung, while fibrinolytic activity is depressed. These abnormalities occur concurrently and favor alveolar fibrin deposition. The systemic derangements of fibrin turnover in sepsis are similar to those that occur in the injured lung. Recent clinical trials demonstrate that interventions using selective anticoagulation can provide a mortality advantage and that selective anticoagulants differ in their ability to provide clinical benefit. Preclinical trials in primates with sepsis-induced ARDS now indicate that anticoagulant interventions that block the extrinsic coagulation pathway can protect against the development of pulmonary fibrin deposition as well as lung dysfunction and acute inflammation. These observations provide proof of principle that key steps in the coagulation cascade are appropriate therapeutic targets to prevent the development of acute lung injury in ARDS. Ongoing studies and prior publications also support the hypothesis that reversal of the fibrinolytic defect in ARDS could protect against the development of acute lung injury. In all, these studies suggest that fibrin deposition in the injured lung as well as abnormalities of coagulation and fibrinolysis are integral to the pathogenesis of ARDS. The ability of selective anticoagulants to effectively and safely alter clinical outcome in ARDS remains to be determined.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal pulmonary disease for which there are no proven drug therapies. Anti-inflammatory and immunosuppressive agents have been largely ineffective. The precise relationship of IPF to other idiopathic interstitial pneumonias (IIPs) is not known, despite the observation that different histopathologic patterns of IIP may coexist in the same patient. We propose that these different histopathologic ‘reaction’ patterns may be determined by complex interactions between host and environmental factors that alter the local alveolar milieu. Recent paradigms in IPF pathogenesis have focused on dysregulated epithelial-mesenchymal interactions, an imbalance in T H 1/T H 2 cytokine profile and potential roles for aberrant angiogenesis. In this review, we discuss these evolving concepts in disease pathogenesis and emerging therapies designed to target pro-fibrogenic pathways in IPF.
Amoxicillin/clavulanic acid 2000mg/125mg extended release (Augmentin XR™), referred to herein as amoxicillin/clavulanic acid XR, is a pharmacokinetically enhanced formulation designed to provide more effective therapy in adults and adolescents than conventional formulations against community-acquired respiratory tract pathogens, particularly Streptococcus pneumoniae , with reduced susceptibility to amoxicillin. Amoxicillin/clavulanic acid XR maintains plasma amoxicillin concentrations >4 μg/mL for a mean of 49% of the dosing interval indicating that it would be highly effective against S. pneumoniae strains with minimum inhibitory concentrations (MICs) above the National Committee for Clinical Laboratory Standard’s amoxicillin ± clavulanic acid susceptibility breakpoint of ≤2 μg/mL. Amoxicillin/clavulanic acid XR is at least as effective as conventional amoxicillin/clavulanic acid formulations, levofloxacin, and clarithromycin in treating community-acquired pneumonia, acute bacterial sinusitis, or acute exacerbations of chronic bronchitis, and has a tolerability profile comparable to that of conventional amoxicillin/clavulanic acid formulations. While the incidence of amoxicillin- or multidrug-resistant S. pneumoniae is not currently sufficient in most regions to warrant the routine empiric use of amoxicillin/clavulanic acid XR, the drug would be extremely useful in those regions with a high incidence of resistant pathogens or in selected patients (i.e. those with S. pneumoniae isolates having amoxicillin MICs ≥2 μg/mL but ≤4 μg/mL).
The treatment of pediatric pulmonary arterial hypertension (PAH) is challenging due to the serious nature of the disease, its rapid progression, and the limited treatment options available. While oral calcium channel antagonists and continuous intravenous epoprostenol have been used successfully for over a decade, novel treatment options — including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors — may change the course of this disease for many children in the future. Prostacyclin analogs offer the benefit over continuous intravenous epoprostenol of an alternative delivery system. However, the efficacy of these medications compared with intravenous epoprostenol and the risk/benefits of each analog need to be weighed in future trials, which need to include larger numbers of pediatric patients to optimize therapy and outcome for individual children with PAH. For patients who do not have an acute response to vasodilator testing or have failed treatment with oral calcium channel antagonists, endothelin receptor antagonists may offer a viable treatment option. Furthermore, in the future, the addition of endothelin receptor antagonists to long-term therapy with calcium channel antagonists or to epoprostenol or a prostacyclin analog may increase the overall efficacy of treatment of PAH. Large multi-institutional randomized trials to determine whether sildenafil is effective and safe for the long-term treatment of PAH in children are in progress. A comprehensive review of these newer agents with an emphasis on the pathobiology/pathophysiology of PAH provides insight into the future management of pediatric PAH patients.
Nosocomial pneumonia or hospital-acquired pneumonia (HAP) causes considerable morbidity and mortality. It is the second most common nosocomial infection and the leading cause of death from hospital-acquired infections. In 1996 the American Thoracic Society (ATS) published guidelines for empirical therapy of HAP. This review focuses on the literature that has appeared since the ATS statement. Early diagnosis of HAP and its etiology is crucial in guiding empirical therapy. Since 1996, it has become clear that differentiating mere colonization from etiologic pathogens infecting the lower respiratory tract is best achieved by employing bronchoalveolar lavage (BAL) or protected specimen brush (PSB) in combination with quantitative culture and detection of intracellular microorganisms. Endotracheal aspirate and non-bronchoscopic BAL/PSB in combination with quantitative culture provide a good alternative in patients suspected of ventilator-associated pneumonia. Since culture results take 2–3 days, initial therapy of HAP is by definition empirical. Epidemiologic studies have identified the most frequently involved pathogens: Enterobacteriaceae, Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus (‘core pathogens’). Empirical therapy covering only the ‘core pathogens’ will suffice in patients without risk factors for resistant microorganisms. Studies that have appeared since the ATS statement issued in 1996, demonstrate several new risk factors for HAP with multiresistant pathogens. In patients with risk factors, empirical therapy should consist of antibacterials with a broader spectrum. The most important risk factors for resistant microorganisms are late onset of HAP (≥5 days after admission), recent use of antibacterial therapy, and mechanical ventilation. Multiresistant bacteria of specific interest are methicillin-resistant S. aureus (MRSA), Pseudomonas aeruginosa, Acinetobacter calcoaceticus- baumannii, Stenotrophomonas maltophilia and extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. Each of these organisms has its specific susceptibility pattern, demanding appropriate antibacterial treatment. To further improve outcomes, specific therapeutic options for multiresistant pathogens and pharmacological factors are discussed. Antibacterials developed since 1996 or antibacterials with renewed interest (linezolid, quinupristin/dalfopristin, teicoplanin, meropenem, new fluoroquinolones, and fourth-generation cephalosporins) are discussed in the light of developing resistance. Since the ATS statement, many reports have shown increasing incidences of resistant microorganisms. Therefore, one of the most important conclusions from this review is that empirical therapy for HAP should not be based on general guidelines alone, but that local epidemiology should be taken into account and used in the formulation of local guidelines.
Leukocyte infiltration of the lung is a characteristic feature of allergic asthma and it is thought that these cells are selectively recruited by chemokines. Extensive research has confirmed that chemokine receptors are expressed on the main cell types involved in asthma, including eosinophils, T helper type 2 cells, mast cells and even neutrophils. Moreover, animal experiments have outlined a functional role for these receptors and their ligands. Chemokines signal via seven-transmembrane spanning G-protein coupled receptors, which are favored targets of the pharmaceutical industry due to the possibility of designing small-molecule inhibitors. In fact, this family represents the first group of cytokines where small-molecule inhibitors have been designed. However, the search for efficient antagonists of chemokine/chemokine receptors has not been easy; a particular feature of the chemokine system is the number of molecules with overlapping functions and binding specificities, as well as the difficulty in reconciling the in vivo biologic functional validation of chemokines in rodent models with the development of antagonists which bind the human receptor, because of the lack of species cross-reactivity. The chemokines and their receptors that are active during allergic reactions are reviewed. Possible points of interaction that may be a target for development of new therapies, as well as the progress to date in developing inhibitors of key chemokine receptors for asthma therapy, are also discussed.
Background: Observational studies have suggested that lung volume reduction surgery (LVRS) is superior to optimal medical therapy for selected subsets of patients with advanced emphysema. Randomized clinical trials (RCTs) with the exception of the National Emphysema Treatment Trial (NETT), failed to enroll a sufficient number of patients to provide clinicians and patients with convincing outcome data on the usefulness of LVRS. It was postulated that a meta-analysis of these RCTs (3–12 months’ follow up) may provide more compelling information on the value of LVRS in patients with emphysema. Methods: A comprehensive search of the MEDLINE database between January 1994 and January 2004 for RCTs on LVRS was performed. Results: From a total of eight RCTs on record, six studies (306 patients) with 3- to 12-month follow up were deemed suitable for meta-analysis. Key baseline features of these RCT populations included heterogeneous emphysema, comparable inclusion/exclusion criteria and, in retrospect, low walking capacity as measured by the 6-minute walk distance (6MWD). This profile closely resembles NETT’s ’predominantly upper lobe — low exercise tolerance emphysema’ cohort. The LVRS arm of the meta-analysis population showed better results than the medical cohort in terms of pulmonary function (FEV 1 p < 0.0001, FVC p < 0.0001, residual volume p < 0.0001, total lung capactiy p = 0.004), gas exchange (arterial partial pressure of oxygen p < 0.0001) and exercise capacity (6MWD p = 0.0002). Although information on quality-of-life measures was not sufficiently uniform to qualify for meta-analysis, a survey of available data revealed better results in the surgical than in the medical arms of each RCT. Mortality 6–12 months after random assignment to treatment was similar in the two study arms, suggesting that the operative mortality from LVRS was offset, within months, by deaths in the medical arm. Conclusions: This meta-analysis showed that a selected subset of patients with advanced, heterogeneous emphysema and low exercise tolerance (6MWD) experienced better outcomes from LVRS than from medical therapy.
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.
Pulmonary alveolar proteinosis (PAP) is characterized by the accumulation of surfactant phospholipids and proteins within the lung alveoli. Important advances have been made over the past 8 years in our understanding of this disease, offering new directions for research and patient care. First, genetically altered mice that are homozygous for a disrupted granulocyte-macrophage colony-stimulating factor (GM-CSF) gene developed a lung lesion with histologic resemblance to PAP. The surfactant is thought to be catabolized or cleared mostly by alveolar macrophages, this process being dependent on GM-CSF. Second, a neutralizing autoantibody against GM-CSF was found in serum and bronchoalveolar lavage fluid of patients with idiopathic PAP but not in healthy controls, thereby raising the suspicion that human PAP may be an autoimmune disease. The relationship between the antibody and disease pathogenesis remains unclear but data suggest that the GM-CSF antibody may have a potential role as a diagnostic test. No specific therapy exists for PAP. Sequential whole lung lavage is the standard of care. Exogenous therapy with GM-CSF may improve the lung disease in some patients with PAP but this therapy is still experimental. Interventions directed at treating a relative GM-CSF deficiency by administration of GM-CSF or lowering the antibody level (i.e. by plasmapheresis or immunosuppression) may hold promise as future therapy for this rare disease.
Non-small cell lung cancer (NSCLC) is cured with surgery in a minority of affected persons. Chemotherapy and radiation can palliate and extend survival of patients with disease not amenable to surgery. Consequently, new treatment options are urgently needed. In the era of molecularly targeted therapeutics, the recent direction in cancer research has been to identify and modulate specific events in tumorigenesis. Angiogenesis, or new vessel formation, is one such event elucidated to be fundamental to the development, growth, and metastasis of cancers and is one of the characteristics that differentiates tumor from host. Thus, targeting of tumor neovasculature continues to generate tremendous enthusiasm and effort in drug development. Extensive research into the role of angiogenesis in NSCLC has produced a host of novel targets; their potential inhibitors, now numbering over 40, are in various phases of clinical testing around the world. The current lead compounds include inhibitors of matrix metalloproteinases, angiogenic growth factors and their receptor tyrosine kinases. Despite their impressive activity in animal models, definitive evidence of their antitumor activity in humans is yet to be established. We face several challenges as we look to advance the field of antiangiogenesis for the treatment of cancer, namely, the need for a better understanding of the optimal timing and dosing of antiangiogenic agents, the validation of imaging and quantification methods of tumor angiogenesis, and a new clinical trials design for a more expedient evaluation of novel cytostatic target modulators.
Idiopathic pulmonary fibrosis (IPF) is a chronic condition of unknown etiology with an unfavorable outcome from progressively deteriorating respiratory function, leading ultimately to death from respiratory failure. It is characterized by sequential acute lung injury resulting in progressive fixed tissue fibrosis, architectural distortion and loss of function. An excess of profibrotic cytokines and/or a deficiency in antifibrotic cytokines have been implicated in the pathological process as has excessive oxidation. IPF is distinguished from other forms of diffuse pulmonary fibrosis by the presence of the specific histological pattern of usual interstitial pneumonitis. Oral corticosteroids are the usual treatment, but objective response rates are poor and good quality studies do not exist. Other therapies either alone or in combination with corticosteroids are widely used, including azathioprine, colchicine, cyclophosphamide and penicillamine. There is a paucity of good quality information regarding the effectiveness of most noncorticosteroid immunosuppressive agents. Older studies of lesser methodological quality have shown benefits from these drugs, generally when added to corticosteroids. Many were retrospective reviews or uncontrolled, nonrandomized, open-label, prospective studies and often included other histological patterns of disease which are now thought to respond better to immunosuppressive agents. The results of intervention with colchicine and azathioprine have been disappointing when assessed by good quality trials using modern diagnostic criteria. Modern high quality studies are lacking for several agents, notably cyclophosphamide and penicillamine. The older agents may yet prove to be effective but further good quality trials will be necessary to assess these agents adequately. Other new anti-inflammatory, antioxidant, antifibrotic or anticytokine compounds are largely untried or unreported. One trial using interferon-γ-1b showed a significant improvement in pulmonary function but there are concerns regarding the generalizability of this study. Pirfenidone, cyclosporine and acetylcysteine may also prove to be of benefit but current studies are of insufficient quality to allow for any conclusions to be drawn. Currently there is no good evidence to support the routine use of oral corticosteroids, azathioprine, cyclophosphamide, penicillamine, colchicine, cyclosporine or any other immunosuppressive, antifibrotic or immunomodulatory agent in the management of IPF. Interferon, pirfenidone and other new agents may be of benefit but further studies are required. Any recommendations for treatment must therefore be made on an individual and empiric basis. As some other forms of pulmonary fibrosis may respond better to immunosuppressive agents, it remains important to make an accurate diagnosis, by open lung biopsy if necessary.
Infection with Legionella spp. is an important cause of serious community- and hospital-acquired pneumonia, occurring sporadically and in outbreaks. Outbreaks of Legionnaires’ disease have recently received considerable media attention, and some factors indicate that the problem will increase in future. Infection with Legionella spp. ranks among the three most common causes of severe pneumonia in the community setting, and is isolated in 1–40% of cases of hospital-acquired pneumonia. Underdiagnosis and underreporting are high. Only 2–10% of estimated cases are reported. Detection of a single case should not be considered an isolated sporadic event, but rather indicative of unrecognized cases. There are no clinical features unique to Legionnaires’ disease; however, suspicion should be raised by epidemiologic information commensurate with the diagnosis and the presence of headache, confusion, hyponatremia, elevated creatine kinase and/or severe pneumonia. An arterial oxygen partial pressure <60mm Hg on presentation and progression of pulmonary infiltrates despite appropriate antibacterial therapy should always alert clinicians to this cause. Macrolides, fluoroquinolones and rifampin (rifampicin) are the most widely used drugs in treatment. Fluoroquinolones or azithromycin are the treatment of choice in immunosuppressed patients and those with severe pneumonia. Incorporation of the legionella urinary antigen test in emergency departments in hospitals and progressive improvement in this test will, in the near future, permit appropriate diagnosis and treatment of this frequent, sometimes severe, illness.
Lung cancer is the second most common cancer and the leading cause of cancer-related deaths in the US. It as been shown that when treated in its early stages, survival rates improve. Despite this, controversy remains regarding screening for the early detection of lung cancer, primarily because mortality reductions were not observed in the trials that studied chest x-ray and sputum cytology. Nevertheless, renewed interest in screening, due in part to better screening options, has prompted further research exploring the potential cost-effectiveness of implementing lung cancer screening programs. This article provides a critical review of the literature of economic evaluations of lung cancer screening programs. The focus of this review is the methodology implemented in these studies. Based on an electronic search of the literature (Pubmed, Medline and CancerLit) from Sep 1988–Sep 2001, seven articles that quantified the cost-effectiveness of lung cancer screening programs were identified. For most of the studies, the cost-effectiveness aspect was a minor component with little or no description of the methods. Although some studies focused more on estimating the economic efficiency of screening, their methodology was weak and still not well documented. Only two studies implemented fully a cost-effectiveness analysis and provided the necessary level of detail. If consensus can be reached regarding the clinical benefit of lung cancer screening, future studies related to cost-effectiveness would have to be implemented on much sounder methodology. The publications reviewed do provide preliminary support for the economic efficiency of screening for lung cancer.
Idiopathic pulmonary arterial hypertension (IPAH) is a rare progressive disorder historically associated with mortality in <3 years post-diagnosis. The etiology of PAH is complex, multifactorial, and likely involves the interplay between genetic and environmental factors. These are reviewed with emphasis on the nitric oxide pathway. Use of treatment modalities including vasodilator therapy have resulted in improved symptoms, hemodynamics, and survival in these patients. Vasodilators, including the calcium channel antagonists, prostanoids, and endothelin receptor antagonists, have been used to counteract potential imbalances in vasoactive mediators in PAH patients; all have produced improved long-term symptomatology and hemodynamics. Only the prostanoid epoprostenol has improved survival in IPAH patients. Although these medications have worked well in many patients with PAH, each of them has limitations. The phosphodiesterase-5 (PDE-5) inhibitors are a relatively new form of treatment for PAH. They are designed to potentiate the effects of cyclic guanosine monophosphate, thereby mimicking endogenous nitric oxide within the vasculature. PDE-5 inhibitors are selective pulmonary vasodilators effective in animal models of pulmonary hypertension. The published clinical studies evaluating their use have been small in size to date but appear to demonstrate benefit. The recently completed 12-week randomized placebo-controlled Sildenafil Use in Pulmonary Hypertension (SUPER-1) trial demonstrated improvement in 6-minute walk distance and hemodynamics in patients receiving sildenafil. These data suggest that the PDE-5 inhibitors are effective in treating PAH and that it is likely that their usage will increase over time. The purpose of this review is to present a current view of the pathogenesis and treatment of PAH, with an emphasis on the use of PDE-5 inhibitors in these patients.
Despite aggressive fixed-dose (FD) combination therapy with inhaled glucocorticosteroids (ICS) and long acting beta(2)-adrenoceptor agonists (LABA), many patients with asthma remain suboptimally controlled, based on the need for rescue therapy and rates of severe exacerbations. The strategy of adjustable maintenance dosing (AMD) involves adjustment of the maintenance dose, (using a single combination [budesonide/formoterol] inhaler, Symbicort((R))) in response to variability of asthma control over time. The AMD strategy, like the FD approach, involves the use of a short-acting beta(2)-adrenoceptor agonist (SABA) for rapid relief of bronchospasm. The dose-response characteristics of budesonide/formoterol make the AMD strategy a feasible option that cannot be exploited with the combination of salmeterol/fluticasone propionate (Advair((R))). Several studies suggest that the AMD strategy is superior to a FD approach in terms of overall asthma control.Budesonide/formoterol in a single inhaler is as effective as albuterol (salbutamol) for relief of acute asthma episodes, a feature that makes it possible to use this combination for both maintenance and reliever therapy without the need for the use of a SABA. The single-inhaler strategy has been shown to be safe and more efficacious than FD therapy. In particular, the COSMOS study has demonstrated that exacerbation burden is reduced more effectively when the combination (budesonide/formoterol) single inhaler is used for both maintenance and relief compared with FD therapy with salmeterol/fluticasone and albuterol for rescue in patients with moderate-to-severe asthma. These findings suggest that we will have to reconsider our definition of reliever therapy for patients that require long-term therapy with combination ICS and LABA.The concept of single-inhaler therapy represents a paradigm shift in asthma management that has been validated in several large studies involving thousands of patients. The single-inhaler strategy represents one of the most significant advances in asthma management in many years, and one that appears ideal for adoption in primary care.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal pulmonary disease for which there are no proven drug therapies. Anti-inflammatory and immunosuppressive agents have been largely ineffective. The precise relationship of IPF to other idiopathic interstitial pneumonias (IIPs) is not known, despite the observation that different histopathologic patterns of IIP may coexist in the same patient. We propose that these different histopathologic ‘reaction’ patterns may be determined by complex interactions between host and environmental factors that alter the local alveolar milieu. Recent paradigms in IPF pathogenesis have focused on dysregulated epithelial-mesenchymal interactions, an imbalance in TH1/TH2 cytokine profile and potential roles for aberrant angiogenesis. In this review, we discuss these evolving concepts in disease pathogenesis and emerging therapies designed to target pro-fibrogenic pathways in IPF.
