Current Respiratory Medicine Reviews - Volume 4, Issue 1, 2008

Daytime fatigue and sleepiness caused by inspiratory flow limitation throughout NREM sleep (with associated arousals), in the absence of the clinical and polysomnographic features of obstructive sleep apnea hypoapnea syndrome (OSA/HS) has been described as the upper airway resistance syndrome (UARS) [1]. Some authors had tried to assign uniqueness to this relatively “young” syndrome, including polysomnographic features (increased alpha frequency during NREM sleep in patients with UARS) and palatal sensory function (intact in patients with UARS) [1,2]. Recent studies have shown that patients with UARS are more somnolent than patients with OSA/H, leading to the hypothesis of a cause-and-effect relationship between airway collapse and physiologic hyperarousals [3]. In one such study, pharyngeal critical pressure (Pcrit) was used as the index of upper airway collapsibility (the airway pressure at the flow-limiting site below which the flow-limiting site collapses). Patients with UARS have been characterized to have lower values of Pcrit when compared with patients with OSA/HS, and just mildly increased when compared to normal individuals [3]. In this issue of Current Respiratory Medicine Reviews, Dr. Guilleminault, the leading expert in UARS presents a comprehensive and up-to-date review on the clinical and pathophysiological variables that define this syndrome [4]. The correct characterization of this syndrome is at times quite difficult for practicing clinicians. There is still some controversy as to whether UARS is a true pathology or an artifact resulting from improper measurement of airflow [3]. The symptoms of UARS include insomnia, daytime sleepiness, sleep fragmentation, and fatigue. In many instances these symptoms may be confused with other pathological entities such as major depression, or chronic fatigue syndrome, or OSA/HS. The UARS has been described to be more frequent among women, in contrast with OSA/HS which is more common among men [1]. The long-term outcome between these two entities is also quite different. When a patient is diagnosed with OSA/H, they get immediate treatment with the lifelong use of a continuous positive airway pressure device. On the other hand, patients that are diagnosed with UARS, in many instances are left untreated [5]. Controversy also arises as whether or not, these patients have accurate hypopnea scores, specifically in patients that have being diagnosed at centers that use thermal sensors [6]. Clearly, more evidence is needed from randomized, controlled trials, to attribute this syndrome its uniqueness and etiopathogenesis. Preliminary studies have tried to outline a theory that would explain if these patients have an abnormal central nervous system response in an attempt to adjust to changes in the upper airway patency during sleep, and that these responses may be genetically predisposed [7]. Whether or not the UARS when properly diagnosed and treated changes the long-term outcome of patients is subject to some debate. However, we believe that this syndrome is still at its infancy and we must address treatment to these patients and look at long-term outcomes......

Respiratory drug particles aerosolized from Dry powder inhalers (DPIs) may charge electrostatically. Influence of electrostatic charge and aerodynamic size distributions on the regional deposition of inhaled aerosols in the lung has been acknowledged by the investigators of aerosol medicine research. This in vitro investigation reports a novel method of simultaneous measurement of both electrostatic charge and aerodynamic diameter of the particle in real time. The drug aerosols were generated by three commercially available and often prescribed DPIs by means of inhalation as a bolus at the rate of 30 L/min for 8 s, and then characterized by a Single Particle Aerodynamic Relaxation Time analyzer. The results showed that particles were not only varied sizes but also carried positive, negative and zero electrostatic charges. Aerosols generated by all three DPIs exhibited net electropositively charged.

In asthma, bronchial mucosal tissues are chronically infiltrated by activated inflammatory cells (mainly lymphocytes and eosinophils) that have the capacity to produce a wide range of cytokines (IL-4, IL-5) and mediators (leucotrienes, prostaglandins, etc.). These molecules may significantly change the functional and phenotypic behavior of resident cells (epithelial cells, fibroblasts, smooth muscle cells, etc.) In addition to their role in tissue repair, resident cells are an important source of cytokines. They play an active role in modulating the immune response, suggesting that they may be involved in the maintenance and chronicity of the inflammatory response. These cells are also involved in structural changes observed in asthma, such as subepithelial fibrosis [3]. The alteration in the structure of the bronchial tree appears to be one of the factors involved in the persistence of bronchial hyperreactivity [4]. This review will focus on the role of structural cells on airway remodeling and their response to asthma medication.

Hematopoietic stem cell transplantation (HSCT) has been employed clinically for the therapy of a wide variety of acquired neoplastic and nonmalignant disorders. However, these immunocompromised patients remain at high risk of developing many serious and often life threatening complications. Occurring in up to 70% of allogeneic HSCT patients, respiratory complications are a leading cause of morbidity and mortality in this population. A rapid identification of the cause and institution of specific therapy is critical to achieve a good outcome. Unfortunately, early recognition and definitive diagnosis of such complications are difficult. In the presence of a modest immune response and neutropenia, the changes on a chest radiograph corresponding to early infectious and non-infectious processes are subtle, nonspecific and may not be recognized. Due to its greater sensitivity, thoracic computed tomography (CT) scan has been proposed to replace the plain chest radiograph (CXR) in the primary evaluation of immunocompromised patients. In the last five years in our institution, thoracic low dose CT (LDCT) scan has become the standard of care and has replaced the CXR in evaluating fever or respiratory symptoms in this group of patients. The published data concerning the use of LDCT scan of the chest as the primary tool for evaluation of this group of patients is limited. Our aim is to summarize the current knowledge in this matter and to add some new perspective from our experience.

Chronic respiratory diseases are one of the leading causes of death and morbidity. Therefore the assessment of regional and global ventilation distribution together with pulmonary perfusion imaging becomes more and more important. To date either radionuclide ventilation scintigraphy or high-resolution computed tomography (HR-CT) are used for ventilation assessment and pulmonary parenchyma analysis. But scintigraphy lacks spatial and temporal resolution while HR-CT applies radiation and lacks functional analysis. Over the last years Magnetic resonance imaging (MRI) of the lung has evolved by using aerosolized contrast agents. MRI offers morphological and functional information and does not apply radiation dose. Approaches to use hyperpolarized gases like Xenon and Helium have been made, but these gases are complex and expensive to produce and use. Lately the use of widely available contrast agents like gadolinium chelates has been investigated. As no special MR hardware is needed and gadolinium is straightforward to apply this new method yields promising results for the future. This review is to give an overview about current developments and methods in Gadolinium-enhanced MR ventilation.

Upper Airway Resistance Syndrome (UARS) was initially used to describe a group of patients who were sleepy but did not meet the diagnostic criteria of obstructive sleep apnea syndrome (OSAS). Since the original description, controversy and ambiguity of this disorder have lead to limited amounts of adequate data and studies. The incidence, prevalence, natural history, and morbidity of this disorder are not well known, and the diagnosis of UARS remains a controversial issue. Advances in technology have lead to measurement of sensitive polysomnographic variables that may aid in effectively identifying this disorder, distinguishing it from OSAS. Recognition of patients with UARS is important because although these patients are symptomatic, they may not present with the same symptoms as patients with OSAS. Treatment options are available that may benefit patients with UARS. This article reviews the pathophysiology, diagnosis, clinical picture and management of UARS.

Respiratory syncytial virus (RSV) is an important pathogen affecting all age groups and has been implicated in the inception of asthma in a subpopulation of children. Despite considerable research, the mechanisms of acute RSV bronchiolitis and post-bronchiolitis wheezing/ asthma are poorly understood and this has hampered efforts for defining risk stratification of patients and development of improved regimens in therapy and prevention. Progress has been made into the identification of molecular pathways involved in RSV pathogenesis, typically by using a traditional “reductionist” approach that focuses on examination of pre-selected targets of interest. By contrast, use of a “systems biology” approach, in which the expression levels and inter-relationships of numerous components of a complex system are interrogated in an unbiased manner, can provide a more global perspective for the identification of novel molecules and pathways for subsequent validation and translation into improved diagnostics and interventions for predictive and personalized medicine. We describe a novel method, consisting of a combination of high-throughput immunoblotting followed by data analysis using GoMiner pathway modeling software, that can screen for RSV-associated alterations in protein expression in multiple cellular pathways, as an example of both the potential and current limitations of using systems biology approaches in the study of RSV infections.

Despite efforts to quell the rising tide of antimicrobial resistance, national trends show disturbing increases in the rate of resistance of clinically relevant microorganisms. The primary basis for this trend is inappropriate or insufficient antimicrobial treatment, which is often due to a lack of rapid diagnostic tools and dependence on time-consuming culturebased approaches for pathogen detection and resistance profiling. Microbial ecologists have long made use of cultureindependent methods to detect unculturable or difficult to culture organisms. More recently, these tools have become more sophisticated and have been applied to a variety of clinical disease and infection states, revealing considerably greater microbial community diversity than previously assumed. Initial reports have revealed that complex microbial communities exist in disparate sites of the body and that shifts in community composition correlate with states of health and disease. Administration of broad-spectrum antibiotics has a pronounced impact on microbial community composition and plays a significant role in the development of antibiotic-resistant organisms. Use of these novel culture-independent approaches has proven invaluable to improving our understanding of microbial community dynamics and presents an enormous potential for rapid diagnosis and temporal monitoring of antimicrobial efficacy. Application of such a technology in a clinical setting could lead to quicker, more accurate diagnosis resulting in a more appropriate therapeutic administration, thus reducing or possibly even reversing the current precipitous rise in antimicrobial resistance.

Lung transplantation provides a successful therapy for end-stage lung disease. However, problems such as acute and chronic lung allograft rejection, the latter also known as bronchiolitis obliterans syndrome (BOS), remain obstacles to achieving better long term outcomes. Novel biomarkers identified in peripheral blood, bronchoalveolar lavage, and lung allograft airway and parenchymal tissue are forwarding progress in the diagnosis of allograft rejection, as well as enhancing our understanding of the immunopathogenesis of BOS. Soluble CD30 levels in peripheral blood reflect T cell activation, and BAL studies with reduced airway-epithelial associated proteins such as CCSP, and increased neutrophil chemotactic factors such as HNPs 1-3 are both linked to BOS. Analysis of transbronchial biopsy specimens for C4d complement deposition, while still in its infancy, seems to help diagnose humoral rejection, which often presents as fulminant respiratory failure and capillaritis. Studies employing basic and translational approaches also now identify a role for innate immunity, as reflected by TLR recipient polymorphisms serving a protective role in the lung allograft. Bacterial and viral infections prevalent in lung allograft recipients through reactivation of endogenous organisms or acquisition of new infections, exert complex immunomodulatory effects, including persistent effector T cell types, which may influence the acquisition or stability of operational tolerance. Disruption of the delicate balance between proteases and inhibitors within the allograft airway submucosa impact upon tissue repair and fibroproliferation evident in BOS. Also of great importance, autoimmunity, as manifest by the ability to recognize self collagen V epitopes, may play a role in acute rejection. Lastly, the application of genomewide profiling, has expanded our ability to understand the biological processes involved in T cell activation, cytokine secretion, and airway injury. ‘On the therapeutic horizon, clinical studies have demonstrated improved treatment of chronic allograft rejection with agents such as inhaled cyclosporine, everolimus, and azithromycin. The widespread use of these and newer compounds awaits additional proof of efficacy from randomized, controlled studies, which, heretofore, have not attracted the attention of prominent funding groups. Ultimately, application of basic, translational, and clinical studies towards the diminution of rejection and/or the achievement of lung allograft tolerance will propel improvements (or gains) in long term patient survival post lung transplantation.

Pulmonary thromboembolism (PTE) ranges from incidental, clinically unimportant thromboembolism to massive embolism with sudden death. Its treatment is well established in two groups of patients: heparin for those with normal systemic blood pressure without right ventricular dysfunction (RVD) and thrombolysis for those with RVD and circulatory shock. In an intermediate group of patients with systemic blood pressure stability combined with RVD, which is usually associated with worse outcome, the treatment is controversial. There are authors who strongly suggest thrombolysis while others contraindicate this procedure and recommend anticoagulation with heparin. This is a narrative review that includes clinical trials comparing thrombolysis and heparin for the treatment of PTE patients with systemic blood pressure stability and RVD published since 1973. The results show that there are only four trials on this subject with less than 500 patients. Many PTE patients with systemic blood pressure stability and RVD might benefit from thrombolysis but, on the other hand, the risk for hemorrhagic events may be increased. Large randomized clinical trials are required to clarify this.

Chronic obstructive pulmonary disease (COPD) is a global health problem. COPD is associated with the progressive pulmonary inflammation and destruction of lung parenchyma (emphysema) that relate to disease severity. Therefore, it is anticipated that drugs that reduce pulmonary inflammation will provide effective, disease modifying therapy for COPD. Several specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD; these include agents directed against cytokines and chemokines. Broad-range antiinflammatory drugs are now in phase III development for COPD; they include inhibitors of phosphodiesterase 4 (PDE4). Other drugs that inhibit cell signaling include inhibitors of p38 mitogen-activated protein kinase (MAPK), nuclear factor- κB (NF-κB), HDAC2 modifiers and phosphoinositide-3-kinase (PI3K). There is also a search for inhibitors of proteinases and matrix metalloproteinases (MMPs) to prevent lung destruction and the development of emphysema. This review highlights the studies on novel or potential anti-inflammatory agents that might be considered in the development of new future therapies for COPD.

Extracorporeal membrane oxygenation (ECMO) is used for severe neonatal and pediatric respiratory failure that fails to respond to maximal therapy, including but not limited to high frequency oscillatory ventilation (HFOV), surfactant replacement, inhaled nitric oxide (NO) and prone positioning of the patient. This report reviews our decade of experience with ECMO and describes various factors that affect the outcome of neonatal and pediatric ECMO for respiratory failure (RF). General clinical and technical concepts regarding ECMO use are also reviewed. We retrospectively evaluated 84 patients, 70 neonatal and 14 pediatric, who were treated with ECMO in our Children's Hospital and showed that the outcome of these patients depends on their underlying pulmonary pathology and the degree of its clinical reversibility. We divided our neonatal and pediatric RF patients into 3 groups: patients with high disease reversibility (Group N1 for neonates and group P1 for pediatric patients), low disease reversibility (groups N2 and P2) and no predicted disease reversibility (groups N3 and P3). The characteristics of the patients and their outcome in these 3 categories are described. Overall, our neonatal ECMO had a better outcome than pediatric ECMO with survival to discharge rates of 76% and 29%, respectively. Patients with neonatal RF without surgically treatable problems in their lungs or ribcages (group N1) had a 92% survival to discharge rate, while neonates with congenital diaphragmatic hernia (group N2) have a survival rate of only 53%. Achieving sustained negative fluid balance during neonatal ECMO of patients in group N1 is an excellent predictor of ECMO success. In pediatric RF the noninfectious etiology for ARDS had a better prognosis (75%) than infectious etiology had (10%). We support the concept that patients who have received more than 7 days of mechanical ventilation for acute respiratory distress syndrome (ARDS) should not be considered for ECMO as their predicted outcome is extremely grave.