Showing papers in "European Respiratory Review in 2007"

Mortality in sleep apnoea syndrome: a review of the evidence

Abstract: Sleep apnoea syndrome is associated with cardiovascular morbidity, but it is less clear if it is also associated with increased mortality. Studies investigating mortality in sleep apnoea have 1) compared mortality rates of patients with different levels of severity of the syndrome relying on sleep laboratory populations, 2) compared treated and untreated patients, 3) examined the effect of co-existing cardiovascular diseases on survival and 4) investigated the effect of sleep-disordered breathing on mortality in the elderly. In spite of methodological limitations, the accumulated data generally support an increased risk of mortality in patients with severe sleep apnoea in comparison with mild or no sleep apnoea, and indicate that efficient treatment decreases mortality. Surprisingly, several studies have shown that the highest risk of mortality in sleep apnoea occurs in patients younger than 50 yrs of age, that risk tends to decline with age and that the occurrence of disordered breathing in sleep in the elderly does not affect mortality. It is as yet unclear if this finding represents a selection bias, differences in apnoea severity or in compliance with treatment between young and old patients, or an adaptation to the syndrome with age. There is conflicting evidence as to whether the occurrence of sleep apnoea in patients with existing cardiovascular diseases increases the risk of mortality beyond that associated with the cardiovascular diseases themselves.

Importance of appropriate initial antibiotic therapy and de-escalation in the treatment of nosocomial pneumonia

Abstract: Inappropriate initial antibiotic therapy in nosocomial pneumonia is associated with higher mortality, longer hospital stays and increased healthcare costs. The key pathogens associated with these adverse outcomes include Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii. Due to the increasing rates of resistance, a new paradigm is needed for treating nosocomial infections in the intensive care unit (ICU). Optimal initial therapy consists of a broad-spectrum antibiotic started in a timely manner and administered at the correct dose and via the correct route. Because pathogen aetiology and resistance patterns vary from one ICU to another, recommendations for initial therapy should be tailored to each institution. Selection of the broad-spectrum antibiotic should be based on the patient's risk factors (including comorbidities, duration of ventilation and recent antibiotic exposure), suspected pathogen and up-to-date local resistance patterns. After 48-72 h, the patient should be reassessed and antibiotic therapy de-escalated based on the microbiological results and the clinical response.

The rationale for treating allergic asthma with anti-IgE

Abstract: An estimated two-thirds of asthma is allergic and >50% of severe asthma has an allergic component. An increased immunoglobulin (Ig)E production in response to environmental allergens (atopy) is the strongest detectable predisposing factor for the development of asthma, particularly when sensitisation occurs early in life. IgE binds to high-affinity receptors (FcϵRI) on effector cells, such as mast cells and basophils. Allergen binds to IgE and initiates an inflammatory cascade resulting in release of pro-inflammatory mediators that contribute to the acute and chronic symptoms of allergic airway diseases. By reducing serum IgE levels and FcϵRI receptor expression on key cells in the inflammatory cascade, omalizumab blocks the release of inflammatory mediators from mast cells and reduces the infiltration of inflammatory cells, notably eosinophils, into the airway. In patients with allergic asthma, omalizumab inhibits both the early and late asthmatic response and several other markers of inflammation, including the requirement for inhaled or oral corticosteroids. The anti-inflammatory effects of omalizumab provide proof-of-concept of the key role played by immunoglobulin E in allergic respiratory disease. Omalizumab represents a novel approach to the treatment of asthma, inhibiting the inflammatory cascade before it starts.

Inflammation in COPD: a link to systemic comorbidities

Abstract: Chronic obstructive pulmonary disease (COPD) has been defined as a preventable and treatable disease characterised by progressive airflow limitation that is not fully reversible and associated with an abnormal inflammatory response in the lungs. Results from a large number of recent studies have characterised the inflammatory processes underlying COPD. Inflammatory cells, most notably CD8+ T-lymphocytes, macrophages and neutrophils, as well as a large number of chemokines, cytokines and proteinases, are believed to play a role. The inflammatory processes in COPD contribute to remodelling of pulmonary tissues, leading to the irreversible airflow limitation characteristic of this disease. Inflammation may also contribute to the comorbidities often observed in COPD patients. Patients with COPD often have cardiovascular disease, changes in body composition, osteoporosis and anaemia. The same inflammatory processes that characterise COPD are also risk factors for these comorbidities. Ongoing studies are evaluating a wide range of new therapies for chronic obstructive pulmonary disease. Some of these have the potential to blunt the inflammatory processes underlying chronic obstructive pulmonary disease and potentially the associated comorbid conditions. These therapies may significantly improve survival, function and quality of life for patients with this disease.

Sleep apnoea and driving: how can this be dealt with?

Abstract: Excessive daytime sleepiness has long been known to be associated with an increased risk of often particularly severe traffic accidents. Obstructive sleep apnoea (OSA) is among the most prevalent conditions leading to excessive daytime sleepiness, in addition to impaired cognitive function, both of which are likely to impair driving ability. An increased risk of traffic accidents has been demonstrated repeatedly, in association with OSA, as well its normalisation with effective treatment. However, it seems that not all patients are at equal risk, but it is not clear how to identify when and how at-risk patients can be identified. Nevertheless, some European countries have made specific regulations concerning OSA and/or excessive daytime sleepiness and the capacity to obtain or to keep a driving license. Most countries have the general rule that “a driving license should not be given or renewed to any candidate or license holder suffering from a disorder … likely to compromise safety on the road”, without a specific mention of sleepiness and/or sleep apnoea. However, the way in which such a statement is applied and the measures taken to identify unfit drivers vary greatly from country to country. In addition, in those countries that have made specific regulations, no evaluation of their efficacy in reducing sleepiness-related accidents is available. In practice, it is the physician9s responsibility to inform the untreated obstructive sleep apnoea patient about the risk associated with their condition, and about the regulations that prevail in their country, if relevant; only in a few countries, is the physician allowed (or compelled) to report the unfit patient to the licensing authorities. Although it is generally accepted that the treated patient may be allowed to drive, the specific treatment conditions that eliminate the risk are not clearly established.

Endothelin: setting the scene in PAH

Abstract: Endothelin (ET), a 21-amino acid peptide secreted by the vascular endothelial cells, is frequently reported to be one of the most potent vasoconstrictors. ET induces endothelial cell, smooth muscle cell and fibroblast dysfunction and is now well recognised as a contributor to the complex pathogenesis of pulmonary arterial hypertension, a devastating chronic disease characterised by progressive vascular remodelling and occlusion of the pulmonary arterioles. ET produces its effects through the stimulation of two receptor subtypes, ET A and ET B , both of which are expressed on smooth muscle cells of pulmonary arterioles. Only the ET B receptor is expressed on vascular endothelial cells. In pre-clinical studies, dual blockade of both receptor subtypes was shown to produce greater inhibition of ET-induced contraction compared with blockade of either of the two receptor subtypes alone. There is also evidence that both the ET A and ET B receptors contribute to pulmonary artery smooth muscle cell proliferation. Pre-clinical research in various models of pulmonary arterial hypertension suggests that simultaneous blockade of the two receptor subtypes would be an effective therapeutic approach in the management of patients with pulmonary arterial hypertension. This has been shown to be the case in a number of randomised controlled clinical trials in pulmonary arterial hypertension due to a number of aetiologies.

Alternatives for OSAHS treatment: selection of patients for upper airway surgery and oral appliances

Abstract: Although continuous positive airway pressure (CPAP) is considered to represent the standard treatment for patients with moderate-to-severe obstructive sleep apnoea/hypopnoea syndrome (OSAHS), poor ...

Examining the unmet need in adults with severe asthma

Abstract: Asthma currently affects an estimated 300 million people worldwide and the number is expected to rise to 400 million by 2025. Asthma morbidity remains high and the economic burden is significant. Approximately 20% of patients have severe persistent asthma. As patients with severe asthma often have a variety of conditions that may coexist with or be mistaken for asthma, careful diagnosis and management are essential, and adhering to a protocol for investigations is helpful. For patients with severe persistent asthma, the Global Initiative for Asthma 2005 guidelines recommend the use of high-dose inhaled corticosteroids in combination with a long-acting β 2 -agonist, with one or more additional controller medications if required (step 4 therapy). However, recent studies have shown that asthma remains inadequately controlled in many patients with severe asthma, despite treatment in accordance with guidelines. Patients with severe asthma have the highest healthcare utilisation and mortality, and there is clearly an unmet need for the effective and safe treatment of patients with severe persistent allergic asthma who remain symptomatic despite optimised standard treatment. The latest guidelines suggest that omalizumab may address this unmet need.

Treatment of obstructive and central sleep apnoea in heart failure: practical options

Abstract: Sleep apnoea, both central and obstructive disordered breathing, commonly occurs in patients with heart failure. Obstructive sleep apnoea occurs both in systolic and diastolic heart failure and is best treated with nasal positive airway pressure devices. Central sleep apnoea occurs primarily in systolic heart failure and therapeutic options are evolving. Optimal therapy of systolic heart failure, nocturnal use of supplemental oxygen, theophylline, acetazolamide and positive airway pressure devices have been shown to improve central sleep apnoea. Among these therapeutic modalities only continuous positive airway pressure has been studied in a long-term trials; unfortunately, it failed to improve survival.

How to evaluate a patient's response to anti-IgE

Abstract: Omalizumab, an anti-immunoglobulin E antibody, is indicated in the European Union (EU) as add-on therapy for patients with severe persistent allergic asthma whose symptoms persist, despite receiving optimised treatment with high-dose inhaled corticosteroids and a long- acting b2-agonist In an attempt to further optimise the use of omalizumab, studies have been performed to investigate whether patient selection for omalizumab therapy could be further enhanced Analyses of pre-treatment baseline variables have shown there is no reliable way to predict which patients within the label population will achieve a greater response to omalizumab However, a physician's overall assessment can easily and reliably identify patients who respond to omalizumab All patients eligible for omalizumab treatment should receive a 16-week trial and treatment should only be continued if the physician judges that a marked improvement in asthma control has been achieved, as specified in the EU label By continuing treatment only in patients who respond to omalizumab therapy, unwarranted drug exposure is minimised, while treatment benefit and cost effectiveness of the therapy are maximised

Where current pharmacological therapies fall short in COPD: symptom control is not enough

Abstract: Chronic obstructive pulmonary disease (COPD) is a common and progressive condition that is currently the fourth leading cause of death worldwide. There is now a large body of evidence indicating that both pulmonary and systemic inflammation are present in patients with stable COPD and may underlie both respiratory symptoms and common comorbidities of this disease. Smoking cessation and long-term oxygen therapy have been shown to change the course of COPD and recent results obtained with the combination of fluticasone and salmeterol have indicated that it could decrease mortality and slow the decline in lung function in patients with this disease. However, some pharmacological treatments can significantly improve dyspnoea, exercise tolerance, limitations in activity, rate of exacerbations and quality of life (e.g. long-acting bronchodilators and inhaled corticosteroids combined with a long-acting b2- agonist). The ability of these agents to modify the rate of disease progression remains to be firmly established in large-scale, long-term trials. The concept of disease modification itself in COPD may need to be revisited and more precisely defined in terms of markers and clinical outcomes, including extrarespiratory manifestations: agents that durably affect symptoms, activities, exacerbations and quality of life should probably be considered as disease modifiers. It is also reasonable to suggest that early diagnosis and treatment of patients with COPD might be the first and potentially most important disease- modifying intervention. There is clearly a need for new therapies that directly target the specific inflammatory processes underlying chronic obstructive pulmonary disease and its pulmonary and extra- pulmonary manifestations.

Optimising the duration of antibiotic therapy for ventilator-associated pneumonia

Abstract: Ventilator-associated pneumonia (VAP) has traditionally been treated with a 14-21- day course of antibiotics. However, prolonged antibiotic therapy is associated with the emergence of multidrug-resistant strains, as well as higher toxicity and costs. In a large, randomised, controlled trial in patients with microbiologically confirmed VAP who received appropriate empirical antibiotic therapy, an 8-day antibiotic regimen was not associated with excess mortality or more episodes of recurrent pulmonary infection compared with a 15-day regimen. Amongst patients who developed recurrent infection, multidrug-resistant pathogens emerged less frequently in the group receiving 8 days of antibiotic therapy. The 8-day regimen was also not associated with excess mortality in the subgroup with VAP caused by nonfermentative Gram-negative bacilli, mostly Pseudomonas aeruginosa, although recurrent infections occurred more often. Pending confirmatory studies, an 8-day course of antibiotic therapy may be appropriate for many patients with ventilator-associated pneumonia, providing that initial antibiotic therapy is appropriate, the clinical course is favourable and extreme vigilance is maintained after stopping antibiotics. Patients whose initial treatment regimen was inappropriate, those infected with difficult-to-treat pathogens such as Pseudomonas aeruginosa, and immunocompromised patients and others at high risk for relapse are likely to require a longer duration of antibiotic therapy.

Pharmacokinetic optimisation of β-lactams for the treatment of ventilator-associated pneumonia

Abstract: Rational therapy of ventilator-associated pneumonia requires choosing the right drug at the right dose. The choice of dose depends on the microbiological goal, the range of minimum inhibitory concentrations (MICs) for likely pathogens, the extent of the drug9s protein binding and, in humans, pharmacokinetics. If protein binding and the distribution of pharmacokinetic parameters are known, as well as the likely pathogens and MICs in a given setting, Monte Carlo simulations can be used to calculate the likelihood that a given dose will attain an identified microbiological goal. For β-lactams, the antibacterial effect depends on the percentage of time (%T) during the dosing interval that the free (nonprotein bound) antibiotic concentration remains above the MIC (%T >MIC); the required values are smaller for carbapenems than for penicillins or cephalosporins. Data show that infusion of an i.v. β-lactam over an extended period may greatly increase %T >MIC, and hence efficacy, at a given dose. Alternatively, it may provide the same efficacy at a lower total dose, reducing cost and potential toxicity. In a real-life setting, a 4-h infusion of 3.375 g piperacillin-tazobactam q8 h (every 8 h; 3 times daily); proved more effective for severe Pseudomonas aeruginosa infections than a 30-min infusion of 3.375 g q6 h (every 6 h; 4 times daily) or q4 h (every 4 h; 6 times daily). Data for doripenem, an investigational carbapenem, suggest that its stability following reconstitution may render it particularly suitable for extended infusion.

Future options for disease intervention: important advances in phosphodiesterase 4 inhibitors

Abstract: Current drug treatments for chronic obstructive pulmonary disease (COPD) focus on managing symptoms of the disease and include short- and long-acting b2-agonists, anticholinergic agents (ipratroprium, tiotropium), methylxanthines (theophylline) and inhaled corticosteroids (ICS). Cyclic nucleotide phosphodiesterases (PDEs) play a key role in cell signalling by degrading cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate. PDE4 is expressed in inflammatory cells and inhibition of this enzyme enhances the anti-inflammatory effects of cAMP in all key cells involved in COPD. Two PDE4 inhibitors, roflumilast and cilomilast, have been extensively evaluated in patients with COPD. Results from patients with moderate-to- severe and severe-to-very severe COPD have shown that roflumilast significantly improves forced expiratory volume in one second (FEV1) and significantly decreases exacerbations, particularly in patients with severe disease. Roflumilast is well tolerated with a low incidence of gastroin- testinal adverse events that declines with continued treatment. Clinical trials with cilomilast have produced more varied results. Significant improvements in FEV1 and reductions in exacerbation rates versus placebo were observed in two of four trials. Cilomilast also has a high risk for gastrointestinal adverse events that does not appear to dissipate over 24 weeks of treatment. While further research is needed to fully determine the place in chronic obstructive pulmonary disease therapy for phosphodiesterase 4 inhibitors, they have several important potential benefits in the treatment of this disease, including convenient once-daily oral administration and freedom from adverse effects associated with corticosteroids. The fact that phosphodiesterase 4 inhibitors have potent anti-inflammatory effects and are administered orally, thereby reaching the systemic circulation, may decrease the severity of systemic comorbidities in chronic obstructive pulmonary disease patients.

Making a diagnosis in PAH

Abstract: Poor survival among patients with untreated pulmonary arterial hypertension (PAH) means that timely and accurate diagnosis is of paramount importance. However, the nonspecific nature of PAH symptoms, which include breathlessness and fatigue, make PAH a considerable diagnostic challenge. As a result, many patients are passed among different physicians and are only correctly diagnosed at relatively advanced stages of disease, when they are already significantly compromised and are finding even the basic activities of daily living difficult. Over recent years, the advent of targeted therapies has changed PAH from a rapidly fatal disease to a serious but treatable condition. This makes the need for obtaining a rapid and accurate diagnosis all the more urgent. The diagnostic process itself requires a reason for clinical suspicion and a series of investigations that are intended to confirm the diagnosis, to establish the cause of pulmonary hypertension and to determine the severity. The present paper reviews the routine investigations available to the physician to diagnose PAH, including electrocardiography, chest radiography, transthoracic Doppler echocardiography and right heart catheterisation, and highlights some of the diagnostic pitfalls encountered en route to an accurate diagnosis of PAH.

Metabolic disturbances in patients with obstructive sleep apnoea syndrome

Abstract: The metabolic disturbances in patients with obstructive sleep apnoea syndrome (OSAS) include insulin resistance and elevated levels of pro-inflammatory cytokines and vascular adhesion molecules, as well as an elevation of hormones derived from the adipose tissue as leptin. These phenomena might, in part, be an explanation for the excess morbidity and mortality of OSAS patients concerning cardiovascular disease. Several of these factors have been described as being independently associated with OSAS and not only related to its comorbidities, including obesity. A promising approach to studying the metabolic phenomena in these OSAS patients would be to monitor patients before and during the course of continuous positive airway pressure therapy, as nocturnal sleep disturbances are treatable and may revert the impact of OSAS on the metabolic phenomena; however, patients do frequently (and unfortunately) maintain their body weight. Although not confirmed by all investigations, a tendency towards an improvement in some of the above-mentioned metabolic parameters has been reported in several studies in obstructive sleep apnoea syndrome patients and may be reflected by the decreased occurrence of new cardiovascular events, the reduction of systolic blood pressure and the improvement of left ventricular systolic function.

Treatment of obstructive sleep-disordered breathing with positive airway pressure systems

Abstract: Positive airway pressure systems are widely used to treat patients with moderate-to-severe obstructive sleep-disordered breathing. The application of stable continuous positive airway pressure (CPAP) via the nose (nasal CPAP) has been the mainstay of treatment since the early 1980s. For treatment to be effective, the pressure level must be fine-tuned to restore patency of the individual patient9s upper airway. Currently, there is ongoing controversy concerning which outcomes to observe when adapting the pressure level, and which methods to use for pressure adaptation. Adjusting the pressure level to control apnoeas and hypopnoeas is one major objective, but may not be sufficient to restore normal sleep. Evidence is available that elimination of inspiratory flow limitation leads to better results. In recent years, it has become evident that the use of empirically set CPAP or automatic CPAP devices parallel the clinical results obtained with the classical approach of manual CPAP titration. A striking and still unexplained paradox lies in the fact that automatic CPAP devices perform very differently on the bench, but still yield satisfactory results on several clinical outcomes, e.g. control of sleep-related respiratory disturbances, restoration of good sleep quality and daytime alertness. Understanding the functioning of automatic CPAP devices can prove difficult, as the mode of operation is usually not disclosed by the manufacturers. At present, it is impossible to make any scientifically sound statement on the appropriateness of using automatic continuous positive airway pressure devices for the routine treatment of patients with obstructive sleep-disordered breathing. For this purpose, convincing results of phase I–III clinical trials are needed.

Anti-IgE: lessons from clinical trials in patients with severe allergic asthma symptomatic despite optimised therapy

Abstract: The efficacy of omalizumab has been extensively investigated in clinical trials in patients with severe persistent allergic (pre-treatment total immunoglobulin E 30-700 IU?mL -1 ) asthma including the Investigation of Omalizumab in Severe Asthma Treatment (INNOVATE) study, which enrolled patients with inadequately controlled severe persistent allergic asthma despite receiving high-dose inhaled corticosteroid in combination with a long-acting b2-agonist, and also additional controller medication if required. In the INNOVATE study, add-on omalizumab significantly reduced clinically significant exacerbation rates by 26% (0.68 versus 0.91), severe exacerbation rates by 50% (0.24 versus 0.48) and emergency visit rates by 44% (0.24 versus 0.43) and significantly improved asthma- related quality of life (QoL) compared with placebo. In a pooled analysis of data from seven studies, add-on omalizumab significantly reduced asthma exacerbation rates by 38% (0.91 versus 1.47) and total emergency visits by 47% (0.332 versus 0.623). In addition, omalizumab significantly improved QoL versus current asthma therapy in a pooled analysis of data from six studies. Omalizumab has demonstrated a good safety and tolerability profile in completed phase-I, -II and -III studies involving .7,500 patients with asthma, rhinitis or related conditions. Omalizumab represents a major advance for the treatment of severe persistent allergic asthma that is inadequately controlled despite treatment with inhaled corticosteroids and a long-acting b2- agonist.

Combination versus monotherapy for nosocomial pneumonia

Abstract: Combination antibiotic therapy of nosocomial pneumonia is sometimes appropriate and desirable; however, it should be used judiciously. When pneumonia appears in the first 5 days following hospital admission and in the absence of other risk factors for infection by multidrug-resistant pathogens, the infection is likely to be due to a pathogen acquired in the community and is likely to be sensitive to most antibiotics. These infections should generally be treated with monotherapy. However, pathogens resistant to multiple drugs are increasingly common in the hospital and intensive care unit setting. In the presence of risk factors for such pathogens, any single drug may prove ineffective; treatment with two or more drugs theoretically increases the likelihood that the pathogen will be sensitive to at least one of them. However, combination therapy also increases the cost and the likelihood of adverse effects, as well as the possibility of drug interactions, if the two are not chosen wisely. The crucial question is whether combination antibiotic therapy actually improves clinical outcome. Most clinical trials suggest that monotherapy and combination therapy provide equivalent efficacy. However, these studies have uniformly excluded the most seriously ill patients: those with Acute Physiology and Chronic Evaluation-II scores >20. It is concluded that available studies provide no concrete evidence to support the use of combination therapy in moderately ill patients and provide no data for the treatment of seriously ill patients who might be most likely to benefit.

Ventilatory support and pharmacological treatment of patients with central apnoea or hypoventilation during sleep

Abstract: The concept of central sleep apnoea or hypoventilation encompasses hypercapnic central hypoventilation, such as obesity hypoventilation syndrome and eucapnic or hypocapnic central sleep apnoea. Among subjects with eucapnic or hypocapnic central sleep apnoea, several therapeutic options are available for those with Cheyne-Stokes respiration (CSR). CSR is frequent in patients with New York Heart Association stage III and IV chronic heart failure, and in various neurological disorders. In these patients, treatment modalities include optimising cardiac condition and drugs, such as theophylline, acetazolamide and/or oxygen. Ventilatory support, such as nasal continuous positive airway pressure (CPAP), bi-level pressure support, or adaptive servo- ventilation (ASV), has been shown to improve CSR in patients with cardiac failure; however, convincing evidence that nasal CPAP improves life expectancy in these patients is lacking. Nevertheless, the treatment of associated obstructive sleep-disordered breathing is indicated per se, as it may improve cardiac function. There is currently no proof that bi-level ventilation is superior to nasal CPAP. The few available studies that have focused on ASV have shown satisfactory control of CSR in cardiac failure patients. While ASV is not a first-line treatment choice, it appears to be superior to oxygen, CPAP and bi-level pressure ventilation in controlling the apnoea/hypopnea index and probably sleep fragmentation. As yet there are no data on mortality and, as such, firm conclusions cannot be drawn as to the role of ASV in the management of cardiac failure patients suffering from CSR. Obesity-related hypoventilation has increased dramatically over recent decades due to the epidemic increase in obesity in the developed countries. Obesity hypoventilation syndrome predisposes to the development of pulmonary hypertension and cor pulmonale. Noninvasive home ventilation is increasingly applied in obese patients with hypercapnic respiratory failure, however, initial mechanical ventilatory support can be reduced to nasal continuous positive airway pressure in only a subset of these individuals.

Blocking endothelin: breaking new ground

Abstract: Endothelin is one of a number of profibrotic cytokines and growth factors, along with transforming growth factor-β, connective tissue growth factor and tumour necrosis factor-α, thought to be involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases characterised by fibrosis, including IPF-related pulmonary hypertension. A growing body of evidence has supported a mitogenic effect of endothelin on fibroblasts and demonstrated that endothelin can reduce collagen breakdown and induce the synthesis of extracellular matrix components, all contributing to fibrosis. These findings, together with the detection of elevated levels of endothelin in the plasma and bronchoalveolar lavage fluid of patients, provide a sound rationale for dual endothelin receptor antagonism as a potential therapy for IPF and other fibrotic lung diseases. The randomised controlled trial of Bosentan Use in Interstitial Lung Disease (BUILD)-1 investigated the potential of bosentan for the treatment of idiopathic pulmonary fibrosis. Although bosentan did not improve exercise capacity, encouraging trends were seen in the pre-defined clinically relevant end-point of disease progression or death, as well as dyspnoea and quality of life measures. The potential efficacy of bosentan, a well-established pathogenic mediator in pulmonary arterial hypertension, will continue to be evaluated in the treatment of idiopathic pulmonary fibrosis.

Treatment effects of sleep apnoea: where are we now?

Abstract: The present article summarises some of the topics of discussion held during one of the workshops in preparation for the 7 th International Symposium of the Katholieke Universiteit Leuven on ''Respiratory somnology: a clinical update; March 2006''. Participants discussed the effectiveness of treatment in obstructive sleep apnoea/hypopnoea syndrome (OSAHS). Of the topics discussed, the following are considered in the present article. 1) Sleepiness and attention deficit, as well as higher cognitive/executive defects in OSAHS, and the closely related clinical dilemma of ''how to deal with the car-driving-ability problem in OSAHS''. 2) Continuous positive airway pressure (CPAP) in post-stroke patients. The most important data discussed during the workshop for 1) and 2) are presented in the present article. 3) The effects of CPAP on metabolic outcome. One metabolic dysfunction of OSAHS is the change in leptin and ghrelin levels, which represent the ''yin and yang'' of an appetite regulatoion system that has developed to inform the brain about the current energy balance state. Data on the impact of sleep loss, either behavioural or OSAHS-related, on this neuroendocrine regulation of appetite are also presented. The participants ended the workshop with a discussion session on the results of more ''controversial'' treatment strategies for obstructive sleep apnoea/hypopnoea syndrome, such as cardiac pacing, hyoid bone expansion (a preliminary surgical technique), drug treatment for obstructive sleep apnoea/hypopnoea syndrome, female hormone replacement therapy and the role of stimulants for refractory sleepiness in already treated obstructive sleep apnoea/ hypopnoea syndrome patients.

Sleep apnoea, hypertension and vascular disease: where are we now?

Abstract: The objective of the present article was to explore the relationship between obstructive sleep apnoea (OSA) and hypertension (HT) and/or arterial vascular disease (VD), including stroke and ischaemic coronary disease. Epidemiological and interventional studies on these relationships provide compelling evidence that OSA is causally related to HT. The causal relationship between OSA and VD other than HT has not been firmly established. A number of pathophysiological mechanisms that could potentially provide a causal link between obstructive sleep apnoea and hypertension, as well as vascular disease, have been identified. Available data on such mechanisms include sustained daytime sympathetic activation, oxidative stress, promotion of vascular inflammation and endothelial dysfunction.

Dual endothelin receptor antagonism: setting standards in PAH

Abstract: Endothelin (ET) has emerged as a key mediator in the pathophysiology of pulmonary arterial hypertension (PAH). The effects of ET are mediated by its binding to two receptors on endothelial and pulmonary smooth muscle cells: ETA and ETB. Blockade of both these receptors with the oral dual ET receptor antagonist, bosentan, represents an attractive treatment option for these severely compromised patients. The efficacy of bosentan in PAH has been demonstrated in randomised controlled trials in idiopathic PAH, and PAH associated with connective tissue diseases and congenital heart disease. In addition, an open-label study has shown clinical and haemodynamic effects in PAH associated with HIV infection. In these trials, bosentan has been shown to improve haemodynamics, increase functional capacity, improve time to clinical worsening, which is a surrogate marker of survival, and to improve patients' quality of life; in longer-term studies, it has been shown to improve patient outcome. The current article will present these key data from randomised controlled trials on bosentan as well as experiences from everyday clinical practice.

Which patients should be treated with anti-IgE?

Abstract: In the European Union, omalizumab is indicated as add-on therapy to improve asthma control in adult and adolescent patients (≥12 yrs of age) with severe persistent allergic asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen, and who, despite receiving daily high-dose inhaled corticosteroids and a long-acting β 2 -agonist, have the following characteristics: reduced lung function (forced expiratory volume in one second −1 . Patients who receive omalizumab should be assessed by their physician after 16 weeks and treatment continued only if there has been a marked improvement in asthma control. Omalizumab is administered by subcutaneous injection every 2 or 4 weeks at a dosage determined using a dosing table based on the patient9s pre-treatment serum total immunoglobulin E levels and body weight.

Confidence from experience: dual endothelin receptor antagonism in PAH

Abstract: Pulmonary hypertension (PH) is classified into five logical treatment-based groups [1]. Pulmonary arterial hypertension (PAH) represents the first of these five groups and is further classified as idiopathic (predisposing factors having been excluded), familial or as occurring in association with certain conditions, including connective tissue disease, congenital heart disease and HIV infection. PAH is characterised by increased pulmonary vascular resistance as a consequence of vascular remodelling, which ultimately leads to right heart failure and death. Few effective medical therapies were available for PAH 10 yrs ago, and in many cases lung transplantation was the only viable treatment option. For patients with idiopathic PAH the outlook was bleak, with relentless deterioration and a predicted 5-yr survival of 22–38% [2]. Thanks to an explosion in research over the last 10 yrs, PAH has changed from an intractable, rapidly fatal condition to a serious but treatable disease. Although the management of patients with PAH remains a therapeutic challenge, the situation …

Challenging cases in PH

Abstract: The requirement for a timely diagnosis of pulmonary arterial hypertension (PAH) to maximise the benefits achieved with appropriate therapy is hampered by the insidious nature of the disease and consequently the late presentation of the majority of patients. Therefore, it is critical to maintain a high index of suspicion in cases of unexplained dyspnoea and to employ a structured and systematic diagnostic strategy. Pulmonary hypertension (PH) has been classified clinically into PAH, PH associated with left heart diseases, PH associated with hypoxaemia or disorders of the respiratory system, PH caused by chronic thrombotic or embolic disease and PH caused by disorders of the pulmonary vasculature, such as sarcoidosis. These different classes of diseases may have similar presentations despite differing physiologies and aetiologies. Moreover, in some cases, incorrect diagnosis and instigation of an inappropriate course of action can have serious consequences. This paper illustrates two particularly challenging clinical cases that can be encountered in patients with pulmonary hypertension.

Respiratory somnology: a clinical update

Abstract: During recent years, it has become evident that disturbed sleep, whether central sleep apnoea syndrome or obstructive sleep-disordered breathing (SDB), may lead to several other effects, such as cardiovascular diseases and many metabolic disturbances. Although the treatment of these sleeping problems is based on ventilatory support and pharmacological agents (in the case of central sleep apnoea or hypoventilation), positive airway pressure systems or upper airway surgery/oral appliances (in the case of obstructive SDB), the treatment effects are not always clear. The treatment effects, in particular on metabolic disturbances, need more investigation, whereas some effects, for instance, on cardiovascular outcome parameters, already seem quite convincing. Related ethical dilemmas may also arise, such as “sleep apnoea and driving”, where it is not always easy to find the optimal solution. The purpose of the international symposium “Respiratory …

Anti-IgE: changing lives in clinical practice?

Abstract: As physicians, we frequently encounter patients with severe persistent asthma who remain symptomatic despite receiving the best available treatment and optimal management efforts. If we are unable to achieve adequate asthma control despite using all available therapeutic options, these patients remain exposed to a high risk of serious exacerbations and asthma-related mortality. Addressing the unmet medical needs of this difficult-to-treat population is one of the greatest challenges in asthma management. Asthma frequently has an allergic component. Immunoglobulin (Ig)E is central to the pathogenesis of allergic asthma and presents an ideal target for novel therapeutic agents. Omalizumab, the first anti-IgE treatment, suppresses IgE-mediated allergic/inflammatory reactions by binding to free IgE. In clinical studies, add-on omalizumab significantly reduced asthma exacerbation rates and the need for emergency medical interventions, and improved quality of life, in patients with severe persistent allergic asthma who were symptomatic despite taking regular high-dose inhaled corticosteroids and long-acting β2-adrenoceptor agonists. I had great pleasure in chairing a Novartis-sponsored satellite symposium entitled “Anti-IgE: changing lives in clinical practice?” at the 16th Annual European Respiratory Society Congress (2006) held in Munich, Germany. The symposium provided an opportunity to bring together a distinguished faculty of experts in the field to discuss the role of anti-IgE therapy in addressing the unmet needs of patients with severe and poorly controlled asthma. In the symposium, we discussed the central role of …