Klaus F. Rabe

Section:ChooseTop of pageAbstract <<CONTENTSINTRODUCTION1. DEFINITION, CLASSIFICA...2. BURDEN OF COPD3. THE FOUR COMPONENTS OF...4. TRANSLATING GUIDELINE ...ReferencesCITING ARTICLES

Allergic rhinitis is a symptomatic disorder of the nose induced after allergen exposure by an immunoglobulin E (IgE)-mediated inflammation of the membranes lining the nose (1). It was defined in 1929 (2): ‘The three cardinal symptoms in nasal reactions occurring in allergy are sneezing, nasal obstruction and mucous discharge’. Allergic rhinitis is a global health problem that causes major illness and disability worldwide. Patients from all countries, all ethnic groups and of all ages suffer from allergic rhinitis. It affects social life, sleep, school and work. The economic impact of allergic rhinitis is often underestimated because the disease does not induce elevated direct costs. However, the indirect costs are substantial (1). Both allergic rhinitis and asthma are systemic inflammatory conditions and are often co-morbidities. Although asthma and other forms of allergic disease have been described in antiquity, ‘hay fever’ is surprisingly modern. Very rare descriptions can be traced back to Islamic texts of the 9th century and European texts of the 16th century. It was only in the early 19th century that the disease was carefully described, and at that time it was regarded as most unusual (3). In the 19th century, the disease followed the industrialization of westernized countries (4). By the end of the 19th century it had become commonplace in both Europe and North America. However, the prevalence of allergic rhinitis was still low and has considerably increased during the past 50 years. In some countries, over 50% of adolescents are reporting symptoms of allergic rhinitis (5). Using a conservative estimate, allergic rhinitis occurs in over 500 million people around the world. The prevalence of allergic rhinitis is increasing in most countries of the world, and particularly in areas with low or medium levels of prevalence. However, it may be plateauing or even decreasing in the highest prevalence areas. Rhinitis and allergic diseases are now taken seriously and the European Union (6) or countries such as Canada have specific programs to better understand, manage and prevent allergic diseases. Risk factors for allergic rhinitis are well identified. In the middle of the 19th century, the cause of hay fever was ascribed to pollens (7, 8). Indoor and outdoor allergens as well as occupational agents cause rhinitis and other allergic diseases. The role of indoor and outdoor pollution is probably very important, but has yet to be fully understood both for the occurrence of the disease and its manifestations. The diagnosis of allergic rhinitis is often easy, but in some cases it may cause problems and many patients are still underdiagnosed, often because they do not perceive the symptoms of rhinitis as a disease impairing their social life, school and work. The management of allergic rhinitis is well established and many guidelines have been issued although the first ones were not evidence based (9–11). In 1999, during the Allergic Rhinitis and its Impact on Asthma (ARIA) World Health Organization (WHO) workshop, the suggestions were made by a panel of experts and based on evidence using an extensive review of the literature available up to December 1999 (1). The statements of evidence for the development of these guidelines followed WHO rules and were based on those of Shekelle et al. (12). The second important achievement of ARIA was to propose a new classification for allergic rhinitis which was subdivided into ‘intermittent’ (IAR) or ‘persistent’ (PER) disease (1). Moreover, it is now recognized that allergic rhinitis comprises more than the classical symptoms of sneezing, rhinorrhoea and nasal obstruction. It is associated with impairments in how patients function in day-to-day life. The severity of allergic rhinitis was therefore classified as ‘mild’ or ‘moderate/severe’ depending on symptoms but also on quality of life (QOL; 1). Another important aspect of the ARIA guidelines was to consider co-morbidities of allergic rhinitis. Eye involvement in allergic rhinitis has been described for a long time (13). The nasal airways and their closely-associated paranasal sinuses are an integral part of the respiratory tract (1, 14–16). In the second century, Claudius Galenus, one of the fathers of modern respiratory physiology, defined the nose as a ‘respiratory instrument’ in his work De usu partium [on the usefulness of the (body) parts (17)]. The co-morbidities between the upper and lower airways were described with the clinical description of allergic rhinitis (3, 8). The nasal and bronchial mucosa present similarities, and one of the most important concepts regarding nose–lung interactions is the functional complementarity (14). Interactions between the lower and the upper airways are well known and have been extensively studied since 1990. Over 80% of asthmatics have rhinitis and 10–40% of patients with rhinitis have asthma (1). Most patients with asthma have rhinitis (18) suggesting the concept of ‘one airway one disease’ although there are differences between rhinitis and asthma (19, 20). The ARIA document was intended to be a state-of-the-art for the specialist as well as for the general practitioner and other healthcare professionals: to update their knowledge of allergic rhinitis; to highlight the impact of allergic rhinitis on asthma; to provide an evidence-based documented revision on diagnostic methods; to provide an evidence-based revision on treatments and to propose a stepwise approach to management. The ARIA document was not intended to be a standard-of-care document for individual countries. It was provided as a basis for doctors, healthcare professionals and organizations involved in the treatment of allergic rhinitis and asthma in various countries to facilitate the development of relevant local standard-of-care documents for patients. The ARIA workshop held at the WHO headquarters proposed the recommendations shown in Table 1. An update of the ARIA guidelines was needed because: a large number of papers have been published over the past 7 years extending our knowledge on the epidemiology, diagnosis, management and co-morbidities of allergic rhinitis. Other guidelines have been produced since 1999 (21), but these did not review the ongoing literature extensively using an evidence-based model; the ARIA recommendations were proposed by an expert group and needed to be validated in terms of classification and management; new evidence-based systems are currently available to guide recommendations and include safety and costs as well as efficacy of treatments (22, 23); there were gaps in our knowledge in the first ARIA document. In particular: some aspects of treatment like complementary and alternative medicine were not appropriately discussed; the links between the upper and lower airways in developing countries and deprived areas were not sufficiently developed even though, in the original ARIA document, a section was written on this subject in collaboration with the UNION (formerly IUATLD); sport and rhinitis in athletes and rhinitis and its links with asthma in preschool children. The ARIA update commenced in 2004. Several chapters of ARIA were extensively reviewed in an evidence-based model, and papers were published (or submitted) in peer-reviewed journals: tertiary prevention of allergy, complementary and alternative medicine, pharmacotherapy and anti-IgE treatment, allergen-specific immunotherapy, links between rhinitis and asthma and mechanisms of rhinitis (24–28). There was then a need for a global document based on the published papers to highlight the interactions between the upper and the lower airways and to: develop an evidence-based global document on a key problem of respiratory medicine including diagnosis, epidemiology, common risk factors, management and prevention; propose educational materials for healthcare professionals and patients; meet the objectives of the WHO Global Alliance against Chronic Respiratory Diseases (GARD; 29) in order to help coordinate the efforts of the different GARD organizations towards a better prevention and management of chronic respiratory diseases (CRD), to increase CRD awareness and also to fill some of the gaps in knowledge; focus on the prevention of chronic respiratory and allergic diseases; highlight gaps in knowledge, particularly in developing countries and deprived areas; prepare an executive summary and pocket guide for doctors, patients and healthcare professionals. Rhinitis is defined as an inflammation of the lining of the nose and is characterized by nasal symptoms including anterior or posterior rhinorrhoea, sneezing, nasal blockage and/or itching of the nose. These symptoms occur during two or more consecutive days for more than 1 h on most days (9). Allergic rhinitis is the most common form of noninfectious rhinitis and is associated with an IgE-mediated immune response against allergens. It is often associated with ocular symptoms. Several nonallergic conditions can cause similar symptoms: infections, hormonal imbalance, physical agents, anatomical anomalies and the use of certain drugs (30). Rhinitis is therefore classified as shown in Table 2 (1). The differential diagnosis of rhinitis is presented in Table 3 (1). Since the nasal mucosa is continuous with that of the paranasal sinuses, congestion of the ostia may result in sinusitis which does not exist without rhinitis. The term ‘rhinosinusitis’ should replace ‘sinusitis’ (31). Vasomotor rhinitis is a term which is not used in this document, as vasomotor symptoms can be caused by allergic and nonallergic rhinitis. Definition and classification of allergic rhinitis Allergic rhinitis is clinically defined as a symptomatic disorder of the nose induced after allergen exposure by an IgE-mediated inflammation. Allergic rhinitis is subdivided into IAR or PER disease. The severity of allergic rhinitis can be classified as ‘mild’ or ‘moderate/severe’. Allergic rhinitis impairs QOL, sleep, school and work. Many nonallergic triggers induce nasal symptoms which mimic allergic rhinitis. They include drugs (aspirin and other nonsteroidal anti-inflammatory agents), occupational agents, foods, physical, emotional and chemical factors and viral infections. 2.2.1.1. Clinical definition. Symptoms of allergic rhinitis include rhinorrhoea, nasal obstruction (32), nasal itching and sneezing which are reversible spontaneously or with treatment (2, 33–36). Postnasal drip mainly occurs either with profuse anterior rhinorrhoea in allergic rhinitis (37) or without significant anterior rhinorrhoea in chronic rhinosinusitis (CRS; 38, 39). Preschool children may just have nasal obstruction. However, when nasal obstruction is the only symptom, it is very rarely associated with allergy. Patients with nonallergic rhinitis may have similar symptoms (40). Allergic rhinitis is subdivided into ‘IAR’ or ‘PER’ disease. The severity of allergic rhinitis can be classified as ‘mild’ or ‘moderate/severe’ (1). 2.2.1.2. Definition for epidemiologic studies. The clinical definition of rhinitis is difficult to use in the epidemiologic settings of large populations where it is impossible to visit everybody individually or to obtain the laboratory evidence of each immune response. However, the standardization of the definition of rhinitis in epidemiologic studies is of crucial importance, especially when comparing the prevalence between studies. Initial epidemiologic studies have assessed allergic rhinitis on the basis of simple ‘working definitions’. Various standardized questionnaires have been used for this effect (41, 42). The first questionnaires assessing seasonal allergic rhinitis dealt with ‘nasal catarrh’ (British Medical Research Council, 1960; 43) and ‘runny nose during spring’ (British Medical Research Council, 1962; 44). Questions introducing the diagnostic term of ‘seasonal allergic rhinitis’ were successively used: ‘Have you ever had seasonal allergic rhinitis?’ or ‘Has a doctor ever told you that you suffer from seasonal allergic rhinitis?’ In the European Community Respiratory Health Survey (ECRHS) full-length questionnaire, the question asked on rhinitis was: ‘Do you have any nasal allergies including “seasonal allergic rhinitis”?’ (45). To identify the responsible allergen, the ECRHS study has included potential triggers of the symptoms. However, this question is not sensitive enough and some patients with nonallergic rhinitis answer ‘yes’. There are however problems with questionnaires. Many patients poorly perceive nasal symptoms of allergic rhinitis: some exaggerate symptoms, whereas many others tend to dismiss the disease (46). Moreover, a large proportion of rhinitis symptoms are not of allergic origin (47). In the Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA), the prevalence of current seasonal allergic rhinitis varied between 9.1% (questionnaire answer and a positive skin prick test to at least one pollen) and 14.2% (questionnaire answer only). Diagnostic criteria affect the reported prevalence rates of rhinitis (48–50). A score considering most of the features of allergic rhinitis (clinical symptoms, season of the year, triggers, parental history, individual medical history and perceived allergy) has recently been proposed (51). Using the doctor’s diagnosis (based on questionnaire, examination and skin tests to common aeroallergens) as a gold standard, these scores had good positive and negative predictive values (84% and 74%, respectively) in the identification of patients suffering from allergic rhinitis. Symptoms of perennial rhinitis have been defined as frequent, nonseasonal, nasal or ocular (‘rhinoconjunctivitis’). In one study, the length of the disease was also taken into consideration to differentiate perennial allergic rhinitis from the ‘common cold’ (viral upper respiratory infections; 52). Objective tests for the diagnosis of IgE-mediated allergy (skin prick test and serum-specific IgE) can also be used (53–55). The diagnostic efficiency of IgE, skin prick tests and Phadiatop® was estimated in 8 329 randomized adults from the SAPALDIA. The skin prick test had the best positive predictive value (48.7%) for the epidemiologic diagnosis of allergic rhinitis compared to the Phadiatop® (43.5%) or total serum IgE (31.6%) (56). Future working definitions may encompass not only clinical symptoms and immune response tests, but also nasal function and eventually specific nasal challenge (57). 2.2.2. Intermittent (IAR) and persistent allergic rhinitis (PER). Previously, allergic rhinitis was subdivided, based on the time of exposure, into seasonal, perennial and occupational (9, 10, 58, 59). Perennial allergic rhinitis is most frequently caused by indoor allergens such as dust mites, molds, insects (cockroaches) and animal danders. Seasonal allergic rhinitis is related to a wide variety of outdoor allergens such as pollens or molds. However, this classification is not entirely satisfactory as: in certain areas, pollens and molds are perennial allergens [e.g. grass pollen allergy in Southern California and Florida (60) or Parietaria pollen allergy in the Mediterranean area (61)]; symptoms of perennial allergy may not always be present all year round. This is particularly the case for a large number of patients allergic to house dust mites (HDM) suffering only from mild or moderate/severe IAR (62–65). This is also the case in the Mediterranean area where levels of HDM allergen are low in the summer (66); the majority of patients are sensitized to many different allergens and therefore exposed throughout the year (33, 62, 67–69). In many patients, perennial symptoms are often present and patients experience seasonal exacerbations when exposed to pollens or molds. It appears therefore that this classification is not adherent to real life; climatic changes modify the time and duration of the pollen season which may make predictions difficult; allergic patients travel and may be exposed to the sensitizing allergens in different times of the year; some patients allergic to pollen are also allergic to molds and it is difficult to clearly define the pollen season (70); some patients sensitized only to a single pollen species have perennial symptoms (71); due to the priming effect on the nasal mucosa induced by low levels of pollen allergens (72–77) and minimal PER inflammation of the nose in patients with symptom-free rhinitis (64, 78, 79), symptoms do not necessarily occur strictly in conjunction with the allergen season and nonspecific irritants such as air pollution may aggravate symptoms in symptomatic patients and induce symptoms in asymptomatic patients with nasal inflammation (80). Thus, a major change in the subdivision of allergic rhinitis was proposed in the ARIA document with the terms ‘IAR’ and ‘PER’ (1). It was shown that the classic types of seasonal and perennial rhinitis cannot be used interchangeably with the new classification of IAR/PER, as they do not represent the same stratum of disease. Thus, ‘IAR’ and ‘PER’ are not synonymous with ‘seasonal’ and ‘perennial’ (36, 62, 67, 81–83). In the original ARIA document, the number of consecutive days used to classify patients with PER was more than four per week (1). However, it appears that patients with PER usually suffer almost every day (84). Whereas the majority of patients have symptoms unrelated to seasons, it is possible to discriminate pollen seasons in some patients. In this case, patients experience symptoms during defined times of the year or have mild PER during most months of the year and more severe symptoms when exposed to high concentrations of allergens during pollen seasons. As most patients are polysensitized, it appears that the ARIA classification is closer to the patients’ needs than the previous one (85). Moreover, PER does not necessarily result from allergic origin (86). 2.2.3.1. Classical symptoms and signs. Allergic rhinitis is characterized by subjective symptoms which may be difficult to quantify due to the fact that they depend largely on the patient’s perception. 2.2.3.2. Symptoms associated with social life, work and school. It is now recognized that allergic rhinitis comprises more than the classical symptoms of sneezing, rhinorrhoea and nasal obstruction. It is associated with impairments in how patients function in day-to-day life. Impairment of QOL is seen in adults (10, 87, 88) and in children (89–92). Patients may also suffer from sleep disorders and emotional problems, as well as from impairment in activities and social functioning (93). Poorly-controlled symptoms of allergic rhinitis may contribute to sleep loss or disturbance (94–104). Moreover, H1-antihistamines with sedative properties can increase sedation in patients with allergic rhinitis (105, 106). Although sleep apnoea syndrome has been associated with nasal disturbances (107–109), it is unclear as to whether allergic rhinitis is associated with sleep apnoea (100, 107, 110). It has been shown that patients with moderate/severe symptoms of IAR or PER have an impaired sleep pattern by comparison to normal subjects and patients with mild rhinitis (111). It is also commonly accepted that allergic rhinitis impairs work (10, 84, 112, 113) and school performance (114–116). In several studies, the severity of allergic rhinitis, assessed using QOL measures, work productivity questionnaires or sleep questionnaires, was found to be somewhat independent of duration (67, 84, 111, 117). 2.2.3.3. Objective measures of severity. Objective measures of the severity of allergic rhinitis include: symptom scores; visual analogue scales (VAS ; 118, 119 ; Fig. 1) ; measurements of nasal obstruction, such as peak inspiratory flow measurements, acoustic rhinometry and rhinomanometry (120–122); measurements of inflammation such as nitric oxide (NO) measurements, cells and mediators in nasal lavages, cytology and nasal biopsy (121, 123); reactivity measurements such as provocation with histamine, methacholine, allergen, hypertonic saline, capsaicin or cold dry air (124) and measurements of the sense of smell (125). Mean mast cells, toludine blue staining, IgE+ and eosinophil cell counts/mm2 nasal biopsy tissues collected from patients with perennial allergic (PAR) and idiopathic (ID) rhinitis, and normal nonrhinitic subjects (N). (Horizontal bar + median counts; St1 = counts in epithelium; St2 = counts in superficial submucosa; St3 = counts in deep submucosa.) (Modified from Powe et al. 2001 (15) and reprinted with kind permission.) Measurements of VAS, nasal obstruction and smell are used in clinical practice. The other measurements are primarily used in research. 2.2.3.4. ARIA classification of allergic rhinitis. In the ARIA classification, allergic rhinitis can be classified as ‘mild’ or ‘moderate/severe’ depending on the severity of the symptoms and their impact on social life, school and work (Table 4). It has also been proposed to classify the severity as ‘mild’, ‘moderate’ or ‘severe’ (36, 126, 127). However, it seems that this proposal makes it more complex for the practicing doctor and does not provide any significant improvement to the patient, this more complex classification failing to translate to a difference in therapeutic options. The severity of allergic rhinitis is independent of its treatment. In asthma, the control level is also independent of asthma medications (128–132). Although such an independent relationship was suspected in a study on allergic rhinitis (67), this very important finding was confirmed in a recent study in which it was found that the severity of rhinitis is independent of its treatment (119). Thus, as for asthma, one of the problems to consider is to replace ‘severity’ by ‘control’, but sufficient data are not yet available. 2.3.1. Infectious rhinitis. For infectious rhinitis, the term rhinosinusitis is usually used. Rhinosinusitis is an inflammatory process involving the mucosa of the nose and one or more sinuses. The mucosa of the nose and sinuses form a continuum and thus, more often than not, the mucous membranes of the sinuses are involved in diseases which are primarily caused by an inflammation of the nasal mucosa. For this reason, infectious rhinitis is discussed under Rhinosinusitis. 2.3.2. Work-related rhinitis. Occupational rhinitis arises in response to an airborne agent present in the workplace and may be due to an allergic reaction or an irritant response (133). Causes include laboratory animals (rats, mice, guinea-pigs, etc.; 134), wood dust, particularly hard woods (Mahogany, Western Red Cedar, etc.; 135), mites (136), latex (137), enzymes (138), grains (bakers and agricultural workers; 139, 140) and chemicals such as acid anhydrides, platinum salts (141), glues and solvents (142). Occupational rhinitis is frequently underdiagnosed due to under-reporting and/or a lack of doctor awareness (133, 143). Diagnosis is suspected when symptoms occur in relation to work. Differentiating between immunologic sensitization and irritation may be difficult. Given the high prevalence of rhinitis in the general population, whatever the cause, then objective tests confirming the occupational origin are essential (144). Measures of inflammatory parameters via nasal lavage and the objective assessment of nasal congestion both offer practical means of monitoring responses (133). Growing experience with acoustic rhinometry and peak nasal inspiratory flow (PNIF) suggests that these methods may have a role in monitoring and diagnosing (145). The surveillance of sensitized workers may enable an early detection of occupational asthma. 2.3.3. Drug-induced rhinitis. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) commonly induce rhinitis and asthma (Table 5). The disease has recently been defined as aspirin-exacerbated respiratory disease (146). In a population-based random sample, aspirin hypersensitivity was more frequent among subjects with allergic rhinitis than among those without (2.6%vs 0.3%; 147). In about 10% of adult patients with asthma, aspirin and other NSAIDs that inhibit cyclo-oxygenase (COX) enzymes (COX-1 and COX-2) precipitate asthma attacks and naso-ocular reactions (148). This distinct clinical syndrome, called aspirin-induced asthma, is characterized by a typical sequence of symptoms: an intense eosinophilic inflammation of the nasal and bronchial tissues combined with an overproduction of cysteinyl leukotrienes (CysLT; 149) and other prostanoids (150, 151). After the ingestion of aspirin or other NSAIDs, an acute asthma attack occurs within 3 hours, usually accompanied by profuse rhinorrhoea, conjunctival injection, periorbital edema and sometimes a scarlet flushing of the head and neck. Aggressive nasal polyposis and asthma run a protracted course, despite the avoidance of aspirin and cross-reacting drugs (152). Blood eosinophil counts are raised and eosinophils are present in nasal mucosa and bronchial airways. Specific anti-COX-2 enzymes are usually well tolerated in aspirin-sensitive patients (149) but many are no longer marketed. A range of other medications is known to cause nasal symptoms. These include: reserpine (154); guanethidine (155); phentolamine (156); methyldopa (155); ACE inhibitors (157); α-adrenoceptor antagonists; intraocular or oral ophthalmic preparations of β-blockers (158); chlorpromazine and oral contraceptives. The term rhinitis medicamentosa (159–161) applies to the rebound nasal obstruction which develops in patients who use intranasal vasoconstrictors chronically. The pathophysiology of the condition is unclear; however, vasodilatation and intravascular edema have both been implicated. The management of rhinitis medicamentosa requires the withdrawal of topical decongestants to allow the nasal mucosa to recover, followed by treatment of the underlying nasal disease (162). Cocaine sniffing is often associated with frequent sniffing, rhinorrhoea, diminished olfaction and septal perforation (163, 164). Amongst the multiuse aqueous nasal, ophthalmic and otic products, benzalkonium chloride is the most common preservative. Intranasal products containing this preservative appear to be safe and well tolerated for both long- and short-term clinical use (165). 2.3.4. Hormonal rhinitis. Changes in the nose are known to occur during the menstrual cycle (166), puberty, pregnancy (167, 168) and in specific endocrine disorders such as hypothyroidism (169) and acromegaly (170). Hormonal imbalance may also be responsible for the atrophic nasal change in postmenopausal women. A hormonal PER or rhinosinusitis may develop in the last trimester of pregnancy in otherwise healthy women. Its severity parallels the blood estrogen level (171). Symptoms disappear at delivery. In a woman with perennial rhinitis, symptoms may improve or deteriorate during pregnancy (172). 2.3.5. Nasal symptoms related to physical and chemical factors. Physical and chemical factors can induce nasal symptoms which may mimic rhinitis in subjects with sensitive mucous membranes and even in normal subjects if the concentration of chemical triggers is high enough (173, 174). Sudden changes in temperature can induce nasal symptoms in patients with allergic rhinitis (175). Chronic effects of cold dry air are important. Skier’s nose (cold, dry air; 176) has been described as a distinct entity. However, the distinction between a normal physiologic response and a disease is not clear and all rhinitis patients may exhibit an exaggerated response to unspecific physical or chemical stimuli. Little information is available on the acute or chronic effects of air pollutants on the nasal mucosa (177). The alterations of physiologic nasal respiration is of importance for any athlete. The impact of exercise on rhinitis and the effect of rhinitis on exercise received considerable attention before the 1984 Olympics, where evidence indicated that chronic rhinitis frequently occurs and deserves specific management in athletes (178). Athletes suffering from symptoms of rhinitis were shown to have impaired performances (179). Many active athletes suffer from allergic rhinitis during the pollen season (180, 181) and most of these receive treatment for their nasal symptoms. On the other hand, some conditions induce nasal symptoms. This is the case of the skier’s nose, a model of cold-induced rhinitis (176, 182–184), or rhinitis in competitive swimmers who inhale large quantities of chlorine gas or hypochlorite liquid (185–187). In runners, nasal resistance falls to about half of its resting values. Decongestion begins immediately after starting running and persists for around 30 min after (27). In multiple chemical sensitivities, nasal symptoms such as impaired odor perception may be present (188). 2.3.6. Rhinitis in smokers. In smokers, eye irritation and odor perception are more common than in nonsmokers (189). Tobacco smoke can alter the mucociliary clearance (190) and can cause an eosinophilic and ‘allergic’-like inflammation in the nasal mucosa of nonatopic children (191). Some smokers report a sensitivity to tobacco smoke including headache, nose irritation (rhinorrhoea, nasal congestion, postnasal drip and sneezing) and nasal obstruction (192). However, in normal subjects, smoking was not found to impair nasal QOL (193). Nonallergic rhinitis with eosinophilia syndrome (NARES) might be caused by passive smoking inducing an ‘allergy-like’ inflammatory response (194). 2.3.7. Food-induced rhinitis. Food allergy is a very rare cause of isolated rhinitis (195). However, nasal symptoms are common among the many symptoms of food-induced anaphylaxis (195). On the other hand, foods and alcoholic beverages in particular may induce symptoms by unknown nonallergic mechanisms. Gustatory rhinitis (hot, spicy food such as hot red pepper; 196) can induce rhinorrhoea, probably because it contains capsaicin. This is able to stimulate

Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. We assessed its efficacy and safety in patients with uncontrolled asthma.We randomly assigned 1902 patients 12 years of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab at a dose of 200 or 300 mg every 2 weeks or matched-volume placebos for 52 weeks. The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the forced expiratory volume in 1 second (FEV1) before bronchodilator use in the overall trial population. Secondary end points included the exacerbation rate and FEV1 in patients with a blood eosinophil count of 300 or more per cubic millimeter. Asthma control and dupilumab safety were also assessed.The annualized rate of severe asthma exacerbations was 0.46 (95% confidence interval [CI], 0.39 to 0.53) among patients assigned to 200 mg of dupilumab every 2 weeks and 0.87 (95% CI, 0.72 to 1.05) among those assigned to a matched placebo, for a 47.7% lower rate with dupilumab than with placebo (P<0.001); similar results were seen with the dupilumab dose of 300 mg every 2 weeks. At week 12, the FEV1 had increased by 0.32 liters in patients assigned to the lower dose of dupilumab (difference vs. matched placebo, 0.14 liters; P<0.001); similar results were seen with the higher dose. Among patients with a blood eosinophil count of 300 or more per cubic millimeter, the annualized rate of severe asthma exacerbations was 0.37 (95% CI, 0.29 to 0.48) among those receiving lower-dose dupilumab and 1.08 (95% CI, 0.85 to 1.38) among those receiving a matched placebo (65.8% lower rate with dupilumab than with placebo; 95% CI, 52.0 to 75.6); similar results were observed with the higher dose. Blood eosinophilia occurred after the start of the intervention in 52 patients (4.1%) who received dupilumab as compared with 4 patients (0.6%) who received placebo.In this trial, patients who received dupilumab had significantly lower rates of severe asthma exacerbation than those who received placebo, as well as better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils. Hypereosinophilia was observed in some patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA QUEST ClinicalTrials.gov number, NCT02414854 .).

Asthma management guidelines provide recommendations for the optimum control of asthma. This survey assessed the current levels of asthma control as reported by patients, which partly reflect the extent to which guideline recommendations are implemented. Current asthma patients were identified by telephone by screening 73,880 households in seven European countries. Designated respondents were interviewed on healthcare utilization, symptom severity, activity limitations and asthma control. Current asthma patients were identified in 3,488 households, and 2,803 patients (80.4%) completed the survey. Forty-six per cent of patients reported daytime symptoms and 30% reported asthma-related sleep disturbances, at least once a week. In the past 12 months, 25% of patients reported an unscheduled urgent care visit, 10% reported one or more emergency room visits and 7% reported overnight hospitalization due to asthma. In the past 4 weeks, more patients had used prescription quick-relief medication (63%) than inhaled corticosteroids (23%). Patient perception of asthma control did not match their symptom severity; approximately 50% of patients reporting severe persistent symptoms also considered their asthma to be completely or well controlled. The current level of asthma control in Europe falls far short of the goals for long-term asthma management. Patients' perception of asthma control is different from their actual asthma control.

Section:ChooseTop of pageAbstract <<COPD PHENOTYPES: AN OPERA...POTENTIAL PHENOTYPESMULTIDIMENSIONAL INDICESWHERE DO WE GO FROM HERE?ReferencesCITING ARTICLES

Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality and represents a substantial economic and social burden throughout the world. It is the fifth leading cause of death worldwide and further increases in its prevalence and mortality are expected in the coming decades. The substantial morbidity associated with COPD is often underestimated by health-care providers and patients; likewise, COPD is frequently underdiagnosed and undertreated. COPD develops earlier in life than is usually believed. Tobacco smoking is by far the major risk for COPD and the prevalence of the disease in different countries is related to rates of smoking and time of introduction of cigarette smoking. Contribution of occupational risk factors is quite small, but may vary depending on a country's level of economic development. Severe deficiency for alpha-1-antitrypsin is rare and the impact of other genetic factors on the prevalence of COPD has not been established. COPD should be considered in any patient presenting with cough, sputum production, or dyspnoea, especially if an exposure to risk factors for the disease has been present. Clinical diagnosis needs to be confirmed by standardised spirometric tests in the presence of not-fully-reversible airflow limitation. COPD is generally a progressive disease. Continued exposure to noxious agents promotes a more rapid decline in lung function and increases the risk for repeated exacerbations. Smoking cessation is the only intervention shown to slow the decline. If exposure is stopped, the disease may still progress due to the decline in lung function that normally occurs with aging, and some persistence of the inflammatory response.

Background: In 1995, the Global Initiative for Asthma (GINA) guidelines recommended goals for the management of asthma, which were updated in 2002.However, there are no recent international surveys on the real management of asthma.Objective: The Asthma Insights and Reality surveys are the first large-scale surveys aimed at determining international variations in the severity, control, and management of asthma in children and adults.Methods: A cross-section of households in 29 countries in North America, Europe, and Asia were surveyed to identify from the general population asthmatic patients with symptoms within the last year or who were taking current asthma medication.A standard questionnaire was administered to 7786 adults, and, through a proxy, to 3153 children with asthma.Objective and subjective patient perception of asthma control and severity were assessed, including access to medical care, health care use, missed work-school, and medication use.Results: Despite variations at a country level, a substantial effect of asthma on patients' lives was observed, with considerable loss of schooldays and workdays.The current level of asthma control worldwide falls far short of the goals for long-term management in international guidelines.A significant proportion of patients continue to have symptoms and lifestyle restrictions and to require emergency care.The proportion of adult asthmatic patients who were current smokers was also high.However, the use of anti-inflammatory preventative medication, even in patients with severe persistent asthma, was low, ranging from 26% in Western Europe to 9% in Japan, as was the use of objective lung function testing.The correlation between self-perceived severity of asthma and objective assessment of severity on the basis of GINA criteria was consistently poor in all areas.Conclusion: We conclude that there is direct evidence for suboptimal asthma control in many patients worldwide, despite the availability of effective therapies, with long-term management falling far short of the goals set in the GINA guidelines.

Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. Its effectiveness in reducing oral glucocorticoid use in patients with severe asthma while maintaining asthma control is unknown.We randomly assigned 210 patients with oral glucocorticoid-treated asthma to receive add-on dupilumab (at a dose of 300 mg) or placebo every 2 weeks for 24 weeks. After a glucocorticoid dose-adjustment period before randomization, glucocorticoid doses were adjusted in a downward trend from week 4 to week 20 and then maintained at a stable dose for 4 weeks. The primary end point was the percentage reduction in the glucocorticoid dose at week 24. Key secondary end points were the proportion of patients at week 24 with a reduction of at least 50% in the glucocorticoid dose and the proportion of patients with a reduction to a glucocorticoid dose of less than 5 mg per day. Severe exacerbation rates and the forced expiratory volume in 1 second (FEV1) before bronchodilator use were also assessed.The percentage change in the glucocorticoid dose was -70.1% in the dupilumab group, as compared with -41.9% in the placebo group (P<0.001); 80% versus 50% of the patients had a dose reduction of at least 50%, 69% versus 33% had a dose reduction to less than 5 mg per day, and 48% versus 25% completely discontinued oral glucocorticoid use. Despite reductions in the glucocorticoid dose, in the overall population, dupilumab treatment resulted in a severe exacerbation rate that was 59% (95% confidence interval [CI], 37 to 74) lower than that in the placebo group and resulted in an FEV1 that was 0.22 liters (95% CI, 0.09 to 0.34) higher. Injection-site reactions were more common with dupilumab than with placebo (9% vs. 4%). Transient blood eosinophilia was observed in more patients in the dupilumab group than in the placebo group (14% vs. 1%).In patients with glucocorticoid-dependent severe asthma, dupilumab treatment reduced oral glucocorticoid use while decreasing the rate of severe exacerbations and increasing the FEV1. Transient eosinophilia was observed in approximately 1 in 7 dupilumab-treated patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA VENTURE ClinicalTrials.gov number, NCT02528214 .).

Many patients with severe asthma rely on oral glucocorticoids to manage their disease. We investigated whether benralizumab, a monoclonal antibody directed against the alpha subunit of the interleukin-5 receptor that significantly reduces the incidence of asthma exacerbations, was also effective as an oral glucocorticoid-sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia.In a 28-week randomized, controlled trial, we assessed the effects of benralizumab (at a dose of 30 mg administered subcutaneously either every 4 weeks or every 8 weeks [with the first three doses administered every 4 weeks]) versus placebo on the reduction in the oral glucocorticoid dose while asthma control was maintained in adult patients with severe asthma. The primary end point was the percentage change in the oral glucocorticoid dose from baseline to week 28. Annual asthma exacerbation rates, lung function, symptoms, and safety were assessed.Of 369 patients enrolled, 220 underwent randomization and started receiving benralizumab or placebo. The two benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P<0.001 for both comparisons). The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as with placebo. Among the secondary outcomes, benralizumab administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P=0.003), and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P<0.001). At 28 weeks, there was no significant effect of either benralizumab regimen on the forced expiratory volume in 1 second (FEV1), as compared with placebo. The effects on various measures of asthma symptoms were mixed, with some showing significant changes in favor of benralizumab and others not showing significant changes. Frequencies of adverse events were similar between each benralizumab group and the placebo group.Benralizumab showed significant, clinically relevant benefits, as compared with placebo, on oral glucocorticoid use and exacerbation rates. These effects occurred without a sustained effect on the FEV1. (Funded by AstraZeneca; ZONDA ClinicalTrials.gov number, NCT02075255 .).

Background The phosphodiesterase-4 inhibitor roflumilast can improve lung function and prevent exacerbations in certain patients with chronic obstructive pulmonary disease (COPD). We therefore investigated whether roflumilast would reduce the frequency of exacerbations requiring corticosteroids in patients with COPD. Methods In two placebo-controlled, double-blind, multicentre trials (M2-124 and M2-125) with identical design that were done in two different populations in an outpatient setting, patients with COPD older than 40 years, with severe airflow limitation, bronchitic symptoms, and a history of exacerbations were randomly assigned to oral roflumilast (500 μg once per day) or placebo for 52 weeks. Primary endpoints were change in prebronchodilator forced expiratory volume in 1 s (FEV1) and the rate of exacerbations that were moderate (glucocorticosteroid-treated) or severe. Analysis was by intention to treat. The trials are registered with ClinicalTrials.gov, number NCT00297102 for M2-124, and NCT00297115 for M2-125. Findings Patients were assigned to treatment, stratified according to smoking status and treatment with longacting β2 agonists, and given roflumilast (n=1537) or placebo (n=1554). In both studies, the prespecified primary endpoints were achieved and were similar in magnitude. In a pooled analysis, prebronchodilator FEV1 increased by 48 mL with roflumilast compared with placebo (p<0·0001). The rate of exacerbations that were moderate or severe per patient per year was 1·14 with roflumilast and 1·37 with placebo (reduction 17% [95% CI 8–25], p<0·0003). Adverse events were more common with roflumilast (1040 [67%]) than with placebo (963 [62%]); 219 (14%) patients in the roflumilast group and 177 (12%) in the placebo group discontinued because of adverse events. In the pooled analysis, the difference in weight change during the study between the roflumilast and placebo groups was −2·17 kg. Interpretation Since different subsets of patients exist within the broad spectrum of COPD, targeted specific therapies could improve disease management. This possibility should be explored further in prospective studies. Funding Nycomed.

Chronic obstructive pulmonary disease (COPD) kills more than 3 million people worldwide every year. Despite progress in the treatment of symptoms and prevention of acute exacerbations, few advances have been made to ameliorate disease progression or affect mortality. A better understanding of the complex disease mechanisms resulting in COPD is needed. Smoking cessation programmes, increasing physical activity, and early detection and treatment of comorbidities are further key components to reduce the burden of the disease. However, without a global political and economic effort to reduce tobacco use, to regulate environmental exposure, and to find alternatives to the massive use of biomass fuel, COPD will remain a major health-care problem for decades to come.

Non-small-cell lung cancer is one of the leading causes of deaths from cancer worldwide. Therefore, improvements in diagnostics and treatments are urgently needed. In this review, we will discuss the evolution of lung cancer staging towards more non-invasive, endoscopy-based, and image-based methods, and the development of stage-adapted treatment. A special focus will be placed on the role of novel surgical approaches and modern radiotherapy strategies for early stages of disease, the effect of multimodal treatment in locally advanced disease, and ongoing developments in the treatment of patients with metastatic disease. In particular, we will include an emphasis on targeted therapies, which are based on the assumption that a treatable driver mutation or gene rearrangement is present within the tumour. Finally, the position of lung cancer treatment on the pathway to personalised therapy will be discussed.

Asthma is a global health problem affecting around 300 million individuals of all ages, ethnic groups and countries. It is estimated that around 250,000 people die prematurely each year as a result of asthma. Concepts of asthma severity and control are important in evaluating patients and their response to treatment, as well as for public health, registries, and research (clinical trials, epidemiologic, genetic, and mechanistic studies), but the terminology applied is not standardized, and terms are often used interchangeably. A common international approach is favored to define severe asthma, uncontrolled asthma, and when the 2 coincide, although adaptation may be required in accordance with local conditions. A World Health Organization meeting was convened April 5-6, 2009, to propose a uniform definition of severe asthma. An article was written by a group of experts and reviewed by the Global Alliance against Chronic Respiratory Diseases review group. Severe asthma is defined by the level of current clinical control and risks as "Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children)." Severe asthma includes 3 groups, each carrying different public health messages and challenges: (1) untreated severe asthma, (2) difficult-to-treat severe asthma, and (3) treatment-resistant severe asthma. The last group includes asthma for which control is not achieved despite the highest level of recommended treatment and asthma for which control can be maintained only with the highest level of recommended treatment.

Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD) but do not specify whether a long-acting anticholinergic drug or a β(2)-agonist is the preferred agent. We investigated whether the anticholinergic drug tiotropium is superior to the β(2)-agonist salmeterol in preventing exacerbations of COPD.In a 1-year, randomized, double-blind, double-dummy, parallel-group trial, we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year.A total of 7376 patients were randomly assigned to and treated with tiotropium (3707 patients) or salmeterol (3669 patients). Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium also increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001). Overall, the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups. There were 64 deaths (1.7%) in the tiotropium group and 78 (2.1%) in the salmeterol group.These results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov number, NCT00563381.).

Chronic obstructive pulmonary disease (COPD) is defined by fixed airflow limitation associated with an abnormal pulmonary and systemic inflammatory response of the lungs to cigarette smoke. The systemic inflammation induced by smoking may also cause chronic heart failure, metabolic syndrome and other chronic diseases, which may contribute to the clinical manifestations and natural history of COPD. Thus COPD can no longer be considered a disease only of the lungs, as it is often associated with a wide variety of systemic consequences. A better understanding of the origin and consequences of systemic inflammation, and of potential therapies, will most likely lead to better care of patients with COPD. Medical textbooks and clinical guidelines still largely ignore the fact that COPD seldom occurs in isolation. As the diagnosis and assessment of severity of COPD may be greatly affected by the presence of comorbid conditions, the current authors believe that lung function measurement, noninvasive assessment of cardiovascular and metabolic functions, and circulating inflammatory markers (e.g. C-reactive protein) might help to better characterise these patients. Similarly, preventive and therapeutic interventions should address the patient in their complexity.

Patients with chronic obstructive pulmonary disease (COPD) have few options for treatment. The efficacy and safety of the phosphodiesterase-4 inhibitor roflumilast have been investigated in studies of patients with moderate-to-severe COPD, but not in those concomitantly treated with longacting inhaled bronchodilators. The effect of roflumilast on lung function in patients with COPD that is moderate to severe who are already being treated with salmeterol or tiotropium was investigated.In two double-blind, multicentre studies done in an outpatient setting, after a 4-week run-in, patients older than 40 years with moderate-to-severe COPD were randomly assigned to oral roflumilast 500 microg or placebo once a day for 24 weeks, in addition to salmeterol (M2-127 study) or tiotropium (M2-128 study). The primary endpoint was change in prebronchodilator forced expiratory volume in 1 s (FEV(1)). Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, number NCT00313209 for M2-127, and NCT00424268 for M2-128.In the salmeterol plus roflumilast trial, 466 patients were assigned to and treated with roflumilast and 467 with placebo; in the tiotropium plus roflumilast trial, 371 patients were assigned to and treated with roflumilast and 372 with placebo. Compared with placebo, roflumilast consistently improved mean prebronchodilator FEV(1) by 49 mL (p<0.0001) in patients treated with salmeterol, and 80 mL (p<0.0001) in those treated with tiotropium. Similar improvement in postbronchodilator FEV(1) was noted in both groups. Furthermore, roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups. Nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal.Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients.Nycomed.

Chronic obstructive pulmonary disease (COPD) is characterised by poorly reversible airflow limitation that is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, particularly cigarette smoke.1 A diagnosis of COPD should be considered in any current or previous smoker older than 40 years who has symptoms of cough, sputum production, or dyspnoea.1 Diagnosis and assessment of severity of COPD are based on the degree of airflow limitation at spirometry.

Smoking cessation has reduced the incidence of lung cancer. The authors of this review discuss recent progress in diagnostic and treatment approaches, including molecular characterization to determine the likelihood of a response to targeted agents and immunotherapies.

<h3>Context</h3>Mediastinal nodal staging is recommended for patients with resectable non–small cell lung cancer (NSCLC). Surgical staging has limitations, which results in the performance of unnecessary thoracotomies. Current guidelines acknowledge minimally invasive endosonography followed by surgical staging (if no nodal metastases are found by endosonography) as an alternative to immediate surgical staging.<h3>Objective</h3>To compare the 2 recommended lung cancer staging strategies.<h3>Design, Setting, and Patients</h3>Randomized controlled multicenter trial (Ghent, Leiden, Leuven, Papworth) conducted between February 2007 and April 2009 in 241 patients with resectable (suspected) NSCLC in whom mediastinal staging was indicated based on computed or positron emission tomography.<h3>Intervention</h3>Either surgical staging or endosonography (combined transesophageal and endobronchial ultrasound [EUS-FNA and EBUS-TBNA]) followed by surgical staging in case no nodal metastases were found at endosonography. Thoracotomy with lymph node dissection was performed when there was no evidence of mediastinal tumor spread.<h3>Main Outcome Measures</h3>The primary outcome was sensitivity for mediastinal nodal (N2/N3) metastases. The reference standard was surgical pathological staging. Secondary outcomes were rates of unnecessary thoracotomy and complications.<h3>Results</h3>Two hundred forty-one patients were randomized, 118 to surgical staging and 123 to endosonography, of whom 65 also underwent surgical staging. Nodal metastases were found in 41 patients (35%; 95% confidence interval [CI], 27%-44%) by surgical staging vs 56 patients (46%; 95% CI, 37%-54%) by endosonography (P = .11) and in 62 patients (50%; 95% CI, 42%-59%) by endosonography followed by surgical staging (P = .02). This corresponded to sensitivities of 79% (41/52; 95% CI, 66%-88%) vs 85% (56/66; 95% CI, 74%-92%) (P = .47) and 94% (62/66; 95% CI, 85%-98%) (P = .02). Thoracotomy was unnecessary in 21 patients (18%; 95% CI, 12%-26%) in the mediastinoscopy group vs 9 (7%; 95% CI, 4%-13%) in the endosonography group (P = .02). The complication rate was similar in both groups.<h3>Conclusions</h3>Among patients with (suspected) NSCLC, a staging strategy combining endosonography and surgical staging compared with surgical staging alone resulted in greater sensitivity for mediastinal nodal metastases and fewer unnecessary thoracotomies.<h3>Trial Registration</h3>clinicaltrials.gov Identifier: NCT00432640

Although in textbooks asthma and chronic obstructive pulmonary disease (COPD) are viewed as distinct disorders, there is increasing awareness that many patients have features of both. This article reviews the asthma-COPD overlap syndrome.

This document provides clinical recommendations for treatment of chronic obstructive pulmonary disease (COPD) exacerbations. Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence relevant to the Task Force's questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of COPD experts. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made: 1) a strong recommendation for noninvasive mechanical ventilation of patients with acute or acute-on-chronic respiratory failure; 2) conditional recommendations for oral corticosteroids in outpatients, oral rather than intravenous corticosteroids in hospitalised patients, antibiotic therapy, home-based management, and the initiation of pulmonary rehabilitation within 3 weeks after hospital discharge; and 3) a conditional recommendation against the initiation of pulmonary rehabilitation during hospitalisation. The Task Force provided recommendations related to corticosteroid therapy, antibiotic therapy, noninvasive mechanical ventilation, home-based management, and early pulmonary rehabilitation in patients having a COPD exacerbation. These recommendations should be reconsidered as new evidence becomes available.

Rationale: The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor (TNF)-α, in severe persistent asthma is unknown.Objectives: To assess the safety and efficacy of golimumab in a large population of patients with uncontrolled, severe persistent asthma.Methods: From 2004 to 2006, 309 patients with severe and uncontrolled asthma, despite high-dose inhaled corticosteroids and long-acting β2 agonists, were randomized 1:1:1:1 to monthly subcutaneous injections of placebo or golimumab (50, 100, or 200 mg) through Week 52. Coprimary endpoints were the change from baseline through Week 24 in prebronchodilator percent-predicted FEV1 and the number of severe asthma exacerbations through Week 24.Measurements and Main Results: No significant differences were observed for the change in percent-predicted FEV1 (least squares mean: placebo, 2.44 [95% confidence interval (CI) −0.574 to 5.461]; combined 100-mg and 200-mg, 2.91 [0.696–5.116]) or severe exacerbations (mean ± SD: placebo, 0.5 ± 1.07 vs. combined 100-mg and 200-mg 0.5 ± 0.97) through week 24. Through Week 24, 2.6% of patients treated with placebo vs. 19.5% of those treated with golimumab discontinued the study agent, and 1.3% and 7.8% discontinued study participation, respectively. An unfavorable risk–benefit profile led to early discontinuation of study-agent administration after the Week-24 database lock. Through Week 76, 20.5% of patients treated with placebo and 30.3% of patients treated with golimumab experienced serious adverse events, with serious infections occurring more frequently in golimumab-treated patients. One death and all eight malignancies occurred in the active groups.Conclusions: Overall, treatment with golimumab did not demonstrate a favorable risk–benefit profile in this study population of patients with severe persistent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT00207740).

Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation associated with chronic inflammation. There are few treatment options for the disease. This study assessed the efficacy and safety of roflumilast, a phosphodiesterase-4 inhibitor, in patients with moderate to severe COPD.This phase III, multicentre, double-blind, randomised, placebo-controlled study was undertaken in an outpatient setting. 1411 patients with COPD were randomly assigned roflumilast 250 microg (n=576), roflumilast 500 microg (n=555), or placebo (n=280) given orally once daily for 24 weeks. Primary outcomes were postbronchodilator FEV1 and health-related quality of life. Secondary outcomes included other lung function parameters and COPD exacerbations. Analyses were by intention to treat.1157 (82%) patients completed the study; 32 (11%) withdrew from the placebo group, 100 (17%) from the roflumilast 250 microg group, and 124 (22%) from the roflumilast 500 microg group. Postbronchodilator FEV1 at the end of treatment significantly improved with roflumilast 250 microg (by 74 mL [SD 18]) and roflumilast 500 microg (by 97 mL [18]) compared with placebo (p<0.0001). Improvement in health-related quality of life was greater with roflumilast 250 microg (-3.4 units [0.6]) and roflumilast 500 microg (-3.5 units [0.6]) than with placebo (-1.8 units [0.8]), although the differences between treatment groups were not significant. The mean numbers of exacerbations per patient were 1.13 (2.37), 1.03 (2.33), and 0.75 (1.89) with placebo, roflumilast 250 microg, and roflumilast 500 microg, respectively. Most adverse events were mild to moderate in intensity and resolved during the study.Roflumilast is a promising candidate for anti-inflammatory COPD treatment because it improved lung function and reduced exacerbations compared with placebo. Long-term studies are needed to fully assess the effect on health-related quality of life.

BackgroundExhaled breath contains thousands of volatile organic compounds (VOCs) that could serve as biomarkers of lung disease. Electronic noses can distinguish VOC mixtures by pattern recognition.ObjectiveWe hypothesized that an electronic nose can discriminate exhaled air of patients with asthma from healthy controls, and between patients with different disease severities.MethodsTen young patients with mild asthma (25.1 ± 5.9 years; FEV1, 99.9 ± 7.7% predicted), 10 young controls (26.8 ± 6.4 years; FEV1, 101.9 ± 10.3), 10 older patients with severe asthma (49.5 ± 12.0 years; FEV1, 62.3 ± 23.6), and 10 older controls (57.3 ± 7.1 years; FEV1, 108.3 ± 14.7) joined a cross-sectional study with duplicate sampling of exhaled breath with an interval of 2 to 5 minutes. Subjects inspired VOC-filtered air by tidal breathing for 5 minutes, and a single expiratory vital capacity was collected into a Tedlar bag that was sampled by electronic nose (Cyranose 320) within 10 minutes. Smellprints were analyzed by linear discriminant analysis on principal component reduction. Cross-validation values (CVVs) were calculated.ResultsSmellprints of patients with mild asthma were fully separated from young controls (CVV, 100%; Mahalanobis distance [M-distance], 5.32), and patients with severe asthma could be distinguished from old controls (CVV, 90%; M-distance, 2.77). Patients with mild and severe asthma could be less well discriminated (CVV, 65%; M-distance, 1.23), whereas the 2 control groups were indistinguishable (CVV, 50%; M-distance, 1.56). The duplicate samples replicated these results.ConclusionAn electronic nose can discriminate exhaled breath of patients with asthma from controls but is less accurate in distinguishing asthma severities.Clinical implicationThese findings warrant validation of electronic noses in diagnosing newly presented patients with asthma. Exhaled breath contains thousands of volatile organic compounds (VOCs) that could serve as biomarkers of lung disease. Electronic noses can distinguish VOC mixtures by pattern recognition. We hypothesized that an electronic nose can discriminate exhaled air of patients with asthma from healthy controls, and between patients with different disease severities. Ten young patients with mild asthma (25.1 ± 5.9 years; FEV1, 99.9 ± 7.7% predicted), 10 young controls (26.8 ± 6.4 years; FEV1, 101.9 ± 10.3), 10 older patients with severe asthma (49.5 ± 12.0 years; FEV1, 62.3 ± 23.6), and 10 older controls (57.3 ± 7.1 years; FEV1, 108.3 ± 14.7) joined a cross-sectional study with duplicate sampling of exhaled breath with an interval of 2 to 5 minutes. Subjects inspired VOC-filtered air by tidal breathing for 5 minutes, and a single expiratory vital capacity was collected into a Tedlar bag that was sampled by electronic nose (Cyranose 320) within 10 minutes. Smellprints were analyzed by linear discriminant analysis on principal component reduction. Cross-validation values (CVVs) were calculated. Smellprints of patients with mild asthma were fully separated from young controls (CVV, 100%; Mahalanobis distance [M-distance], 5.32), and patients with severe asthma could be distinguished from old controls (CVV, 90%; M-distance, 2.77). Patients with mild and severe asthma could be less well discriminated (CVV, 65%; M-distance, 1.23), whereas the 2 control groups were indistinguishable (CVV, 50%; M-distance, 1.56). The duplicate samples replicated these results. An electronic nose can discriminate exhaled breath of patients with asthma from controls but is less accurate in distinguishing asthma severities.

Abstract Antimicrobial peptides produced by epithelial cells and neutrophils represent essential elements of innate immunity, and include the defensin and cathelicidin family of antimicrobial polypeptides. The human cathelicidin cationic antimicrobial protein-18 is an antimicrobial peptide precursor predominantly expressed in neutrophils, and its active peptide LL-37 is released from the precursor through the action of neutrophil serine proteinases. LL-37 has been shown to display antimicrobial activity against a broad spectrum of microorganisms, to neutralize LPS bioactivity, and to chemoattract neutrophils, monocytes, mast cells, and T cells. In this study we show that LL-37 activates airway epithelial cells as demonstrated by activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and increased release of IL-8. Epithelial cell activation was inhibited by the MAPK/ERK kinase (MEK) inhibitors PD98059 and U0126, by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478, by blocking anti-EGFR and anti-EGFR-ligand Abs, and by the metalloproteinase inhibitor GM6001. These data suggest that LL-37 transactivates the EGFR via metalloproteinase-mediated cleavage of membrane-anchored EGFR-ligands. LL-37 may thus constitute one of the mediators by which neutrophils regulate epithelial cell activity in the lung.

Background The contributions of as-needed inhaled corticosteroids and long-acting β2 agonists (LABA) to asthma control have not been fully established. We compared the efficacy and safety of three reliever strategies: a traditional short-acting β2 agonist; a rapid-onset LABA (formoterol); and a combination of LABA and an inhaled corticosteroid (budesonide-formoterol) in symptomatic patients receiving budesonide-formoterol maintenance therapy. Methods We did a 12-month, double-blind, parallel-group study in 3394 patients (aged 12 years or older), in 289 centres in 20 countries, who were using inhaled corticosteroids at study entry and symptomatic on budesonide-formoterol (160 μg and 4·5 μg, respectively), one inhalation twice daily, during a 2-week run-in. After run-in, patients were randomly assigned budesonide-formoterol maintenance therapy plus one of three alternative as-needed medications—terbutaline (0·4 mg), formoterol (4·5 μg), or budesonide-formoterol (160 μg and 4·5 μg). The primary outcome was time to first severe exacerbation, defined as an event resulting in hospitalisation, emergency room treatment, or both, or the need for oral steroids for 3 days or more. Findings Time to first severe exacerbation was longer with as-needed budesonide-formoterol versus formoterol (p=0·0048; log-rank test) and with as-needed formoterol versus terbutaline (p=0·0051). The rate of severe exacerbations was 37, 29, and 19 per 100 patients per year with as-needed terbutaline, formoterol, and budesonide-formoterol, respectively (rate ratios budesonide-formoterol versus formoterol 0·67 [95% CI 0·56–0·80; p<0·0001]; budesonide-formoterol versus terbutaline 0·52 [0·44–0·62; p<0·0001]; formoterol versus terbutaline 0·78 [0·67–0·91; p=0·0012]). Asthma control days increased to a similar extent in all treatment groups. As-needed formoterol did not significantly improve symptoms compared with as-needed terbutaline. All treatments were well tolerated. Interpretation Both monocomponents of budesonide-formoterol given as needed contribute to enhanced protection from severe exacerbations in patients receiving combination therapy for maintenance.

<h2>Summary</h2><h3>Background</h3> Exhaled breath contains thousands of gaseous volatile organic compounds (VOCs) that may be used as non-invasive markers of lung disease. The electronic nose analyzes VOCs by composite nano-sensor arrays with learning algorithms. It has been shown that an electronic nose can distinguish the VOCs pattern in exhaled breath of lung cancer patients from healthy controls. We hypothesized that an electronic nose can discriminate patients with lung cancer from COPD patients and healthy controls by analyzing the VOC-profile in exhaled breath. <h3>Methods</h3> 30 subjects participated in a cross-sectional study: 10 patients with non-small cell lung cancer (NSCLC, [age 66.4±9.0, FEV₁ 86.3±20.7]), 10 patients with COPD (age 61.4±5.5, FEV₁ 70.0±14.8) and 10 healthy controls (age 58.3±8.1, FEV₁ 108.9±14.6). After 5min tidal breathing through a non-rebreathing valve with inspiratory VOC-filter, subjects performed a single vital capacity maneuver to collect dried exhaled air into a Tedlar bag. The bag was connected to the electronic nose (Cyranose 320) within 10min, with VOC-filtered room air as baseline. The smellprints were analyzed by onboard statistical software. <h3>Results</h3> Smellprints from NSCLC patients clustered distinctly from those of COPD subjects (cross validation value [CVV]: 85%; M-distance: 3.73). NSCLC patients could also be discriminated from healthy controls in duplicate measurements (CVV: 90% and 80%, respectively; M-distance: 2.96 and 2.26). <h3>Conclusion</h3> VOC-patterns of exhaled breath discriminates patients with lung cancer from COPD patients as well as healthy controls. The electronic nose may qualify as a non-invasive diagnostic tool for lung cancer in the future.

Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β2-agonist (LABA) for chronic obstructive pulmonary disease (COPD) have been studied at single dose levels of inhaled glucocorticoid, but studies at two dose levels are lacking.In a 52-week, phase 3, randomized trial to evaluate the efficacy and safety of triple therapy at two dose levels of inhaled glucocorticoid in patients with moderate-to-very-severe COPD and at least one exacerbation in the past year, we assigned patients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 μg or 160 μg of budesonide], a LAMA [18 μg of glycopyrrolate], and a LABA [9.6 μg of formoterol]) or one of two dual therapies (18 μg of glycopyrrolate plus 9.6 μg of formoterol or 320 μg of budesonide plus 9.6 μg of formoterol). The primary end point was the annual rate (the estimated mean number per patient per year) of moderate or severe COPD exacerbations, as analyzed in the modified intention-to-treat population with the use of on-treatment data only.The modified intention-to-treat population comprised 8509 patients. The annual rates of moderate or severe exacerbations were 1.08 in the 320-μg-budesonide triple-therapy group (2137 patients), 1.07 in the 160-μg-budesonide triple-therapy group (2121 patients), 1.42 in the glycopyrrolate-formoterol group (2120 patients), and 1.24 in the budesonide-formoterol group (2131 patients). The rate was significantly lower with 320-μg-budesonide triple therapy than with glycopyrrolate-formoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69 to 0.83; P<0.001) or budesonide-formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79 to 0.95; P = 0.003). Similarly, the rate was significantly lower with 160-μg-budesonide triple therapy than with glycopyrrolate-formoterol (25% lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; P<0.001) or budesonide-formoterol (14% lower: rate ratio, 0.86; 95% CI, 0.79 to 0.95; P = 0.002). The incidence of any adverse event was similar across the treatment groups (range, 61.7 to 64.5%); the incidence of confirmed pneumonia ranged from 3.5 to 4.5% in the groups that included inhaled glucocorticoid use and was 2.3% in the glycopyrrolate-formoterol group.Triple therapy with twice-daily budesonide (at either the 160-μg or 320-μg dose), glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD exacerbations than glycopyrrolate-formoterol or budesonide-formoterol. (Funded by AstraZeneca, ETHOS ClinicalTrials.gov number, NCT02465567.).

Roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease. Its effect in patients using fixed combinations of inhaled corticosteroids and longacting β2 agonists is unknown. We postulated that roflumilast would reduce exacerbations in patients with severe chronic obstructive pulmonary disease at risk for exacerbations, even in combination with inhaled corticosteroid and longacting β2 agonist treatment.For this 1-year double-blind, placebo-controlled, parallel group, multicentre, phase 3-4 trial, the Roflumilast and Exacerbations in patients receiving Appropriate Combination Therapy (REACT) study, we enrolled patients with severe chronic obstructive pulmonary disease from 203 centres (outpatient clinics, hospitals, specialised pulmonologists, and family doctors) in 21 countries. Eligible patients were 40 years of age or older with a smoking history of at least 20 pack-years and a diagnosis of chronic obstructive pulmonary disease with severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year. We used a computerised central randomisation system to randomly assign patients in a 1:1 ratio to the two treatment groups: roflumilast 500 μg or placebo given orally once daily together with a fixed inhaled corticosteroid and longacting β2 agonist combination. Background tiotropium treatment was allowed. All patients and investigators were masked to group assignment. The primary outcome was the rate of moderate to severe chronic obstructive pulmonary disease exacerbations per patient per year, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329029.Between April 3, 2011, and May 27, 2014, we enrolled 1945 eligible participants and randomly assigned 973 to the roflumilast group and 972 to the placebo group. The rate of moderate-to-severe chronic obstructive pulmonary disease exacerbations was 13·2% lower in the roflumilast group than in the placebo group according to a Poisson regression analysis (roflumilast 0·805 vs placebo 0·927; rate ratio [RR] 0·868 [95% CI 0·753-1·002], p=0·0529), and 14·2% lower according to a predefined sensitivity analysis using negative binomial regression (0·823 vs 0·959; 0·858 [0·740-0·995], p=0·0424). Adverse events were reported by 648 (67%) of 968 patients receiving roflumilast and by 572 (59%) of 967 patients in the placebo group; adverse event-associated patient withdrawal from the study was also more common in the roflumilast group (104/968 [11%]) than in the placebo group (52/967 [5%]). The most frequently reported serious adverse events were chronic obstructive pulmonary disease exacerbations and pneumonia, and 17 (1·8%) deaths occurred in the roflumilast group compared with 18 (1·9%) in the placebo group.Our findings suggest that roflumilast reduces exacerbations and hospital admissions in patients with severe chronic obstructive pulmonary disease and chronic bronchitis who are at risk of frequent and severe exacerbations despite inhaled corticosteroid and longacting β2 agonist therapy, even in combination with tiotropium.Takeda.

Temporal resolution of cellular features associated with a severe COVID-19 disease trajectory is needed for understanding skewed immune responses and defining predictors of outcome. Here, we performed a longitudinal multi-omics study using a two-center cohort of 14 patients. We analyzed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. Validation was performed in two independent cohorts of COVID-19 patients. Severe COVID-19 was characterized by an increase of proliferating, metabolically hyperactive plasmablasts. Coinciding with critical illness, we also identified an expansion of interferon-activated circulating megakaryocytes and increased erythropoiesis with features of hypoxic signaling. Megakaryocyte- and erythroid-cell-derived co-expression modules were predictive of fatal disease outcome. The study demonstrates broad cellular effects of SARS-CoV-2 infection beyond adaptive immune cells and provides an entry point toward developing biomarkers and targeted treatments of patients with COVID-19.

Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive fibrotic interstitial lung diseases (ILDs)) other than IPF. In view of the pathomechanistic and clinical similarities between IPF and other progressive fibrotic ILDs, we aimed to assess the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic ILDs.We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18-80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40-90% predicted, a diffusing capacity of the lung for carbon monoxide of 10-90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6-24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebo-controlled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32; DRKS00009822 and is no longer recruiting.Between April 5, 2016, and Oct 4, 2018, we randomly assigned 127 patients to treatment: 64 to pirfenidone, 63 to placebo. After 127 patients had been randomised, the study was prematurely terminated on the basis of an interim analysis for futility triggered by slow recruitment. After 48 weeks and in the overall population of 127 patients, rank ANCOVA with diagnostic group included as a factor showed a significantly lower decline in FVC % predicted in the pirfenidone group compared with placebo (p=0·043); the result was similar when the model was stratified by diagnostic group (p=0·042). A significant treatment effect was also observed when applying the LOCF and multiple imputation methods to analyses of the primary endpoint. The median difference (Hodges-Lehmann estimate) between pirfenidone and placebo groups for the primary endpoint was 1·69 FVC % predicted (95% CI -0·65 to 4·03). In the linear mixed-model repeated measures slope analysis of FVC % predicted, the estimated difference between treatment and placebo groups from baseline to week 48 was 3·53 FVC % predicted (95% CI 0·21 to 6·86) with imputation of deaths as prespecified, or 2·79 FVC % predicted (95% CI 0·03 to 5·54) without imputation. One death (non-respiratory) occurred in the pirfenidone group (2%) and five deaths (three of which were respiratory) occurred in the placebo group (8%). The most frequent serious adverse events in both groups were infections and infestations (five [8%] in the pirfenidone group, ten [16%] in the placebo group); general disorders including disease worsening (two [3%] in the pirfenidone group, seven [11%] in the placebo group); and cardiac disorders (one ([2%] in the pirfenidone group, 5 [8%] in the placebo group). Adverse events (grade 3-4) of nausea (two patients on pirfenidone, two on placebo), dyspnoea (one patient on pirfenidone, one on placebo), and diarrhoea (one patient on pirfenidone) were also observed.In view of the premature study termination, results should be interpreted with care. Nevertheless, our data suggest that in patients with fibrotic ILDs other than IPF who deteriorate despite conventional therapy, adding pirfenidone to existing treatment might attenuate disease progression as measured by decline in FVC.German Center for Lung Research, Roche Pharma.

The term severe refractory asthma (SRA) in adults applies to patients who remain difficult to control despite extensive re-evaluation of diagnosis and management following an observational period of at least 6 months by a specialist. Factors that influence asthma control should be recognized and adequately addressed prior to confirming the diagnosis of SRA. This report presents statements according to the literature defining SRA in order address the important questions. Phenotyping SRA will improve our understanding of mechanisms, natural history, and prognosis. Female gender, obesity, and smoking are associated with SRA. Atopy is less frequent in SRA, but occupational sensitizers are common inducers of new-onset SRA. Viruses contribute to severe exacerbations and can persist in the airways for long periods. Inflammatory cells are in the airways of the majority of patients with SRA and persist despite steroid therapy. The T(H)2 immune process alone is inadequate to explain SRA. Reduced responsiveness to corticosteroids is common, and epithelial cell and smooth muscle abnormalities are found, contributing to airway narrowing. Large and small airway wall thickening is observed, but parenchymal abnormalities may influence airway limitation. Inhaled corticosteroids and bronchodilators are the mainstay of treatment, but patients with SRA remain uncontrolled, indicating a need for new therapies.

Omalizumab is a monoclonal antibody indicated for treatment of severe persistent allergic asthma inadequately controlled despite optimal controller therapy. We investigated whether patient selection could be targeted further.Data from seven randomized controlled omalizumab trials were analyzed to investigate whether pre-treatment patient baseline clinical characteristics could be identified that were predictive of a superior response to omalizumab. We also studied whether patients who respond to omalizumab following a course of treatment could be reliably identified. Univariate/multivariate analyses of INNOVATE data were performed to identify predictive baseline measures and further investigated in efficacy analyses of pooled data from seven studies. The best method of identifying responders to omalizumab following treatment was determined by assessing the ability of various clinical response criteria to identify responders and discriminate patient exacerbation and other outcomes.Baseline total immunoglobulin E (IgE) was the only predictor of efficacy in INNOVATE. However, pooled analysis showed treatment benefits irrespective of IgE levels. In omalizumab-treated patients, physician's overall assessment following a course of treatment identified 61% as responders and best discriminated treatment outcomes.Baseline characteristics do not reliably predict benefit with omalizumab. Physician's overall assessment after 16 weeks of treatment is the most meaningful measure of response to therapy.

Inhaled corticosteroids have been used in patients with chronic obstructive pulmonary disease (COPD), but the potential benefits of their use in triple therapy are not well known. We aimed to compare the efficacy of a triple therapy with corresponding dual therapies in symptomatic patients with moderate to very severe COPD, without a requirement for a history of exacerbations.In this double-blind, parallel-group, multicentre phase 3 randomised controlled trial, we recruited patients from hospitals and care centres in Canada, China, Japan, and the USA. Eligible patients were 40-80 years of age, were current or former smokers (with a smoking history of ≥10 pack-years), had an established clinical history of COPD, and were symptomatic for COPD, despite receiving two or more inhaled maintenance therapies for at least 6 weeks before screening. We randomly assigned patients (2:2:1:1) using an interactive web response system to receive budesonide/glycopyrrolate/formoterol fumarate metered-dose inhaler 320/18/9·6 μg (BGF MDI), glycopyrrolate/ formoterol fumarate metered-dose inhaler 18/9·6 μg (GFF MDI), budesonide/formoterol fumarate metered-dose inhaler 320/9·6 μg (BFF MDI), or open-label budesonide/formoterol fumarate dry-powder inhaler 400/12 μg (BUD/ FORM DPI). Primary endpoints for the Europe/Canada statistical analysis approach were FEV1 area under the curve from 0-4 h (AUC0-4) for BGF MDI versus BFF MDI and BGF MDI versus BUD/FORM DPI over 24 weeks; and change from baseline in morning pre-dose trough FEV1 for BGF MDI versus GFF MDI and non-inferiority of BFF MDI versus BUD/FORM DPI (margin of -50 mL from lower bound of 95% CI) over 24 weeks. Comparisons with BUD/FORM DPI were made for the Europe/Canada statistical analysis approach only. This study is registered with ClinicalTrials.gov, number NCT02497001.Between Aug 20, 2015, and Jan 5, 2018, 3047 patients were screened from 215 sites, and 1902 were randomly assigned to receive BGF MDI (n=640), GFF MDI (n=627), BFF MDI (n=316), or BUD/FORM DPI (n=319). Over 24 weeks, BGF MDI significantly improved FEV1 AUC0-4 versus BFF MDI (least squares mean difference 104 mL, 95% CI 77 to 131; p<0·0001) and BUD/FORM DPI (91 mL, 64 to 117; p<0·0001). BGF MDI also significantly improved pre-dose trough FEV1 versus GFF MDI (22 mL, 4 to 39; p=0·0139) and was non-inferior to BUD/FORM DPI (-10 mL, -36 to 16; p=0·4390). At week 24, patients in the BGF MDI group had a significantly improved FEV1 AUC0-4 compared with patients receiving BFF MDI (116 mL, 95% CI 80 to 152; p<0·0001); there was a non-significant improvement in the change from baseline in morning pre-dose trough FEV1 at week 24 versus GFF MDI (13 mL, -9 to 36 mL; p=0·2375). The most common treatment-emergent adverse events were nasopharyngitis (n=49 [8%] in the BGF MDI group; n=41 [7%] in the GFF MDI group; n=26 [8%] in the BFF MDI group; and n=30 [9%] in the BUD/FORM DPI group) and upper respiratory tract infection (n=65 [10%]; n=38 [6%]; n=18 [6%]; and n=22 [7%]). Pneumonia incidence was low (<2%) and similar across treatments. There were two treatment-related deaths, both in the GFF MDI group.BGF MDI was efficacious, well tolerated, and could be a more appropriate treatment than the corresponding dual therapies for symptomatic patients with moderate to very severe COPD, irrespective of exacerbation history.Pearl-a member of the AstraZeneca Group.

Small airways dysfunction (SAD) is well recognised in asthma, yet its role in the severity and control of asthma is unclear. This study aimed to assess which combination of biomarkers, physiological tests, and imaging markers best measure the presence and extent of SAD in patients with asthma.In this baseline assessment of a multinational prospective cohort study (the Assessment of Small Airways Involvement in Asthma [ATLANTIS] study), we recruited participants with and without asthma (defined as Global Initiative for Asthma severity stages 1-5) from general practices, the databases of chest physicians, and advertisements at 29 centres across nine countries (Brazil, China, Germany, Italy, Spain, the Netherlands, the UK, the USA, and Canada). All participants were aged 18-65 years, and participants with asthma had received a clinical diagnosis of asthma more than 6 months ago that had been confirmed by a chest physician. This diagnosis required support by objective evidence at baseline or during the past 5 years, which could be: positive airway hyperresponsiveness to methacholine, positive reversibility (a change in FEV1 ≥12% and ≥200 mL within 30 min) after treatment with 400 μg of salbutamol in a metered-dose inhaler with or without a spacer, variability in peak expiratory flow of more than 20% (measured over 7 days), or documented reversibility after a cycle (eg, 4 weeks) of maintenance anti-asthma treatment. The inclusion criteria also required that patients had stable asthma on any previous regular asthma treatment (including so-called rescue β2-agonists alone) at a stable dose for more than 8 weeks before baseline and had smoked for a maximum of 10 pack-years in their lifetime. Control group participants were recruited by advertisements; these participants were aged 18-65 years, had no respiratory symptoms compatible with asthma or chronic obstructive pulmonary disease, normal spirometry, and normal airways responsiveness, and had smoked for a maximum of 10 pack-years. We assessed all participants with spirometry, body plethysmography, impulse oscillometry, multiple breath nitrogen washout, CT (in selected participants), and questionnaires about asthma control, asthma-related quality of life (both in participants with asthma only), and health status. We applied structural equation modelling in participants with asthma to assess the contribution of all physiological and CT variables to SAD, from which we defined clinical SAD and CT SAD scores. We then classified patients with asthma into SAD groups with model-based clustering, and we compared asthma severity, control, and health-care use during the past year by SAD score and by SAD group. This trial is registered with ClinicalTrials.gov, number NCT02123667.Between June 30, 2014, and March 3, 2017, we recruited and evaluated 773 participants with asthma and 99 control participants. All physiological measures contributed to the clinical SAD model with the structural equation modelling analysis. The prevalence of SAD in asthma was dependent on the measure used; we found the lowest prevalence of SAD associated with acinar airway ventilation heterogeneity (Sacin), an outcome determined by multiple breath nitrogen washout that reflects ventilation heterogeneity in the most peripheral, pre-acinar or acinar airways. Impulse oscillometry and spirometry results, which were used to assess dysfunction of small-sized to mid-sized airways, contributed most to the clinical SAD score and differed between the two SAD groups. Participants in clinical SAD group 1 (n=452) had milder SAD than group 2 and comparable multiple breath nitrogen washout Sacin to control participants. Participants in clinical SAD group 2 (n=312) had abnormal physiological SAD results relative to group 1, particularly their impulse oscillometry and spirometry measurements, and group 2 participants also had more severe asthma (with regard to asthma control, treatments, exacerbations, and quality of life) than group 1. Clinical SAD scores were higher (indicating more severe SAD) in group 2 than group 1, and we found that these scores were related to asthma control, severity, and exacerbations. We found no correlation between clinical SAD and CT SAD scores.SAD is a complex and silent signature of asthma that is likely to be directly or indirectly captured by combinations of physiological tests, such as spirometry, body plethysmography, impulse oscillometry, and multiple breath nitrogen washout. SAD is present across patients with all severities of asthma, but it is particularly prevalent in severe disease. The clinical classification of SAD into two groups (a milder and a more severe group) by use of impulse oscillometry and spirometry, which are easy to use, is meaningful given its association with GINA severity stages, asthma control, quality of life, and exacerbations.Chiesi Farmaceutici SpA.

COPD is characterized by a poorly reversible airflow limitation resulting from chronic inflammation, mainly due to tobacco exposure. Over the past few years, the understanding of COPD has evolved from it being a disease affecting the lungs to it being a complex, heterogeneous, and generalized disorder in an aging population. Extrapulmonary comorbidities significantly complicate the management and influence the prognosis of patients with COPD. Although certain comorbidities like cardiovascular diseases share some risk factors with COPD, such as cigarette smoking, other frequently observed comorbidities, including musculoskeletal wasting, metabolic syndrome, and depression, cannot be easily attributed to smoking. There is increasing evidence that chronic inflammation is a key factor in COPD and that inflammation might be the common pathway linking these comorbidities and explaining why they typically develop together. Physicians treating patients with COPD need to become aware of these extrapulmonary aspects. Any patient with COPD should be carefully evaluated for comorbidities and the systemic consequences of COPD since they not only influence the prognosis but also have an impact on disease management. The treatment of COPD is no longer focused exclusively on inhaled therapy but is taking on a multidimensional approach, especially because the treatment of the comorbidities might positively affect the course of COPD itself.

Phosphodiesterase 4 (PDE4) is a member of the PDE enzyme superfamily that inactivates cyclic adenosine monophosphate and cyclic guanosine monophosphate, and is the main PDE isoenzyme occurring in cells involved in inflammatory airway disease such as chronic obstructive pulmonary disease (COPD). COPD is a preventable and treatable disease and is characterized by airflow obstruction that is not fully reversible. Chronic progressive symptoms, particularly dyspnoea, chronic bronchitis and impaired overall health are worse in those who have frequent, acute episodes of symptom exacerbation. Although several experimental PDE4 inhibitors are in clinical development, roflumilast, a highly selective PDE4 inhibitor, is the first in its class to be licensed, and has recently been approved in several countries for oral, once‐daily treatment of severe COPD. Clinical trials have demonstrated that roflumilast improves lung function and reduces exacerbation frequency in COPD. Furthermore, its unique mode of action may offer the potential to target the inflammatory processes underlying COPD. Roflumilast is effective when used concomitantly with all forms of bronchodilator and even in patients treated with inhaled corticosteroids. Roflumilast thus represents an important addition to current therapeutic options for COPD patients with chronic bronchitis, including those who remain symptomatic despite treatment. This article reviews the current status of PDE4 inhibitors, focusing on the pharmacokinetics, efficacy and safety of roflumilast. In particular, it provides an overview of the effects of roflumilast on lung function and exacerbations, glucose homoeostasis and weight loss, and the concomitant use of long‐acting beta 2 ‐adrenergic receptor agonists and short‐acting muscarinic receptor antagonists. LINKED ARTICLES This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue‐1

Tissue verification of noncaseating granulomas is recommended for the diagnosis of sarcoidosis. Bronchoscopy with transbronchial lung biopsies, the current diagnostic standard, has moderate sensitivity in assessing granulomas. Endosonography with intrathoracic nodal aspiration appears to be a promising diagnostic technique.To evaluate the diagnostic yield of bronchoscopy vs endosonography in the diagnosis of stage I/II sarcoidosis.Randomized clinical multicenter trial (14 centers in 6 countries) between March 2009 and November 2011 of 304 consecutive patients with suspected pulmonary sarcoidosis (stage I/II) in whom tissue confirmation of noncaseating granulomas was indicated.Either bronchoscopy with transbronchial and endobronchial lung biopsies or endosonography (esophageal or endobronchial ultrasonography) with aspiration of intrathoracic lymph nodes. All patients also underwent bronchoalveolar lavage.The primary outcome was the diagnostic yield for detecting noncaseating granulomas in patients with a final diagnosis of sarcoidosis. The diagnosis was based on final clinical judgment by the treating physician, according to all available information (including findings from initial bronchoscopy or endosonography). Secondary outcomes were the complication rate in both groups and sensitivity and specificity of bronchoalveolar lavage in the diagnosis of sarcoidosis.A total of 149 patients were randomized to bronchoscopy and 155 to endosonography. Significantly more granulomas were detected at endosonography vs bronchoscopy (114 vs 72 patients; 74% vs 48%; P < .001). Diagnostic yield to detect granulomas for endosonography was 80% (95% CI, 73%-86%); for bronchoscopy, 53% (95% CI, 45%-61%) (P < .001). Two serious adverse events occurred in the bronchoscopy group and 1 in the endosonography group; all patients recovered completely. Sensitivity of the bronchoalveolar lavage for sarcoidosis based on CD4/CD8 ratio was 54% (95% CI, 46%-62%) for flow cytometry and 24% (95% CI, 16%-34%) for cytospin analysis.Among patients with suspected stage I/II pulmonary sarcoidosis undergoing tissue confirmation, the use of endosonographic nodal aspiration compared with bronchoscopic biopsy resulted in greater diagnostic yield.clinicaltrials.gov Identifier: NCT00872612.

Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) frequently occur together and their coexistence is associated with worse outcomes than either condition alone. Pathophysiological links between COPD and CVD include lung hyperinflation, systemic inflammation and COPD exacerbations. COPD treatments may produce beneficial cardiovascular (CV) effects, such as long-acting bronchodilators, which are associated with improvements in arterial stiffness, pulmonary vasoconstriction, and cardiac function. However, data are limited regarding whether these translate into benefits in CV outcomes. Some studies have suggested that treatment with long-acting β2-agonists and long-acting muscarinic antagonists leads to an increase in the risk of CV events, particularly at treatment initiation, although the safety profile of these agents with prolonged use appears reassuring. Some CV medications may have a beneficial impact on COPD outcomes, but there have been concerns about β-blocker use leading to bronchospasm in COPD, which may result in patients not receiving guideline-recommended treatment. However, there are few data suggesting harm with these agents and patients should not be denied β-blockers if required. Clearer recommendations are necessary regarding the identification and management of comorbid CVD in patients with COPD in order to facilitate early intervention and appropriate treatment.

We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.

Little is known about the role of physical activity in the course of chronic obstructive pulmonary disease (COPD).To assess changes in physical activity in COPD in relation to severity stages and changes in other disease components, and to evaluate the longitudinal association between sustained physical inactivity and disease progression.In this prospective cohort study, we measured physical activity (multisensory armband), airflow obstruction (FEV1), health status (St. George's Respiratory Questionnaire), exercise capacity (6-min-walk distance [6MWD]), muscle mass (fat-free mass [FFM]), and systemic inflammation (fibrinogen and high-sensitivity C-reactive protein) over a 3-year period in 137 patients with COPD and 26 with chronic bronchitis (normal spirometry).Independent of baseline disease severity, steps per day, total daily energy expenditure, and (daily) physical activity level (PAL) decreased by 393, 76 kcal, and 0.04 per year, respectively. The decline in PAL was significantly associated with a decline in FEV1 and an increase in St. George's Respiratory Questionnaire total score. Changes in 6MWD, FFM, and inflammatory markers were not associated with changes in PAL. Independent of FEV1, sustained physical inactivity (i.e., PAL(T0andT1) < 1.40) was related to a greater decline in 6MWD and FFM compared with that in patients with some level of activity (i.e., PAL(T0and/orT1) ≥ 1.40; difference, 17 m/yr and 0.87 kg/yr, respectively).Over time, physical activity substantially decreases across all severity stages of COPD, and this decline is paralleled by a worsening of lung function and health status. Sustained physical inactivity is associated with a progression of exercise intolerance and muscle depletion.

Asthma is the most prevalent chronic respiratory disease both in children and adults and resembles a complex syndrome rather than a single disease. Different methods have been developed to better characterise distinct asthma phenotypes in childhood and adulthood. In studies of adults, most phenotyping relies on biomaterials from the lower airways; however, this information is missing in paediatric studies because of restricted accessibility. Few patients show symptoms throughout childhood, adolescence, and adulthood. Risk factors for this might be genetics, family history of asthma and atopy, infections early in life, allergic diseases, and lung function deficits. In turn, a large proportion of children with asthma lose their symptoms during school age and adolescence. This improved prognosis, which might also reflect a better treatment response, is associated with being male and with milder and less allergic disease. Importantly, whether clinical remission of symptoms equals the disappearance of underlying pathology is unknown. In fact, airway hyper-responsiveness and airway inflammation might remain despite the absence of overt symptoms. Additionally, a new-onset of asthma symptoms is apparent in adulthood, especially in women and in the case of impaired lung function. However, many patients do not remember childhood symptoms, which might reflect relapse rather than true initiation. Both relapse and adult-onset of asthma symptoms have been associated with allergic disease and sensitisation in addition to airway hyper-responsiveness. Thus, asthma symptoms beginning in adults might have originated in childhood. Equivocally, persistence into, relapse, and new-onset of symptoms in adulthood have all been related to active smoking. However, underlying mechanisms for the associations remain unclear, and future asthma research should therefore integrate standardised molecular approaches in identical ways in both paediatric and adult populations and in longitudinal studies.

The efficacy, safety and positioning of inhaled corticosteroids (ICS) in the treatment of patients with chronic obstructive pulmonary disease (COPD) is much debated, since it can result in clear clinical benefits in some patients ("friend") but can be ineffective or even associated with undesired side effects, e.g. pneumonia, in others ("foe"). After critically reviewing the evidence for and against ICS treatment in patients with COPD, we propose that: 1) ICS should not be used as a single, stand-alone therapy in COPD; 2) patients most likely to benefit from the addition of ICS to long-acting bronchodilators include those with history of multiple or severe exacerbations despite appropriate maintenance bronchodilator use, particularly if blood eosinophils are >300 cells·µL-1, and those with a history of and/or concomitant asthma; and 3) the risk of pneumonia in COPD patients using ICS is higher in those with older age, lower body mass index (BMI), greater overall fragility, receiving higher ICS doses and those with blood eosinophils <100 cells·µL-1 All these factors must be carefully considered and balanced in any individual COPD patient before adding ICS to her/his maintenance bronchodilator treatment. Further research is needed to clarify some of these issues and firmly establish these recommendations.

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Background Combinations of long-acting bronchodilators are recommended to reduce the rate of chronic obstructive pulmonary disease (COPD) exacerbations. It is unclear whether combining olodaterol, a long-acting beta-agonist, with tiotropium, a long-acting anti-muscarinic, reduces the rate of exacerbations compared with tiotropium alone. Methods This 52-week, double-blind, randomised, parallel-group, active-controlled trial randomly assigned (1:1) patients with COPD with a history of exacerbations using a randomised block design to receive tiotropium–olodaterol 5 μg–5 μg or tiotropium 5 μg once daily. Patients using inhaled corticosteroids continued this therapy. Treatment was masked to patients, investigators, and those involved in analysing the data. The primary endpoint was the rate of moderate and severe COPD exacerbations from the first dose of medication until 1 day after last drug administration. The primary analysis included all randomly assigned patients who received any dose of study medication but were not from a site excluded due to on-site protocol violations. The trial is registered with ClinicalTrials.gov, number NCT02296138. Findings Overall, 9009 patients were screened from 818 centres in 51 countries. We recruited 7880 patients between Jan 22, 2015 and March 7, 2016 (mean age 66·4 years [SD 8·5], 5626 [71%] were men, mean FEV1 percent predicted 44·5% [SD 27·7]): 3939 received tiotropium–olodaterol and 3941 tiotropium. The rate of moderate and severe exacerbations was lower with tiotropium–olodaterol than tiotropium (rate ratio [RR] 0·93, 99% CI 0·85–1·02; p=0·0498), not meeting the targeted 0·01 significance level. The proportion of patients reporting adverse events was similar between treatments. Interpretation Combining tiotropium and olodaterol did not reduce exacerbation rate as much as expected compared with tiotropium alone. Funding Boehringer Ingelheim International GmbH.

Dupilumab, a fully human anti-IL-4Rα monoclonal antibody, inhibits signaling of both interleukin (IL)-4 and IL-13, which are key drivers of type 2-mediated inflammation. Dupilumab is approved in the EU, USA, and other countries for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis. Following positive phase 2 results in asthma, the phase 3 Liberty Asthma QUEST trial was initiated to provide further evidence for dupilumab efficacy and safety in patients with uncontrolled, moderate-to-severe asthma.Liberty Asthma QUEST is a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (NCT02414854) in patients with persistent asthma who are receiving continuous treatment with inhaled corticosteroids (ICS) plus one or two other asthma controller medicines. A total of 1902 patients (aged ≥ 12 years) were randomized in a 2:2:1:1 ratio to receive 52 weeks of add-on therapy with subcutaneously administered dupilumab 200 or 300 mg every 2 weeks or matched placebo. The study consisted of a 4 ± 1-week screening period, 52-week randomized treatment period, and 12-week post-treatment follow-up period. All patients continued to receive their prescribed ICS plus up to two additional controller medications. The primary efficacy endpoints were annualized rate of severe exacerbation events during the 52-week treatment period and absolute change from baseline in pre-bronchodilator FEV1 at week 12.Uncontrolled asthma patients with persistent symptoms represent a population of significant unmet need, for whom new treatments are required. Patients with severe asthma are at high risk of asthma exacerbations, and face an accelerated decline in lung function and impaired quality of life. QUEST examines the efficacy of dupilumab in this at-risk patient population; it is the largest placebo-controlled study in uncontrolled, moderate-to-severe asthma with a biologic agent to date, and the only phase 3 study of a biologic therapy of asthma that enrolled patients irrespective of baseline type 2 inflammatory biomarker levels.Sanofi and Regeneron Pharmaceuticals, Inc. CLINICAL TRIALS.NCT02414854.

Rationale: In the phase III, 52-week ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial in chronic obstructive pulmonary disease (COPD) (NCT02465567), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) significantly reduced all-cause mortality compared with glycopyrrolate/formoterol fumarate (GFF). However, 384 of 8,509 patients were missing vital status at Week 52 in the original analyses.Objectives: To assess the robustness of the ETHOS mortality findings after additional data retrieval for patients missing Week 52 vital status in the original analyses.Methods: Patients with moderate to very severe COPD and prior history of exacerbation received twice-daily dosing with 320/18/9.6 μg of BGF (BGF 320), 160/18/9.6 μg of BGF (BGF 160), 18/9.6 μg of GFF, or 320/9.6 μg of budesonide/formoterol fumarate (BFF) (all delivered via a single metered-dose Aerosphere inhaler). Time to death (all-cause) was a prespecified secondary endpoint.Measurements and Main Results: In the final retrieved dataset, which included Week 52 vital status for 99.6% of the intent-to-treat population, risk of death with BGF 320 was significantly lower than GFF (hazard ratio, 0.51; 95% confidence interval, 0.33–0.80; unadjusted P = 0.0035). There were no significant differences in mortality when comparing BGF 320 with BFF (hazard ratio, 0.72; 95% confidence interval, 0.44–1.16; P = 0.1721), nor were significant differences observed when comparing BGF 160 against either dual comparator. Results were similar when the first 30, 60, or 90 days of treatment were excluded from the analysis. Deaths from cardiovascular causes occurred in 0.5%, 0.8%, 1.4%, and 0.5% of patients in the BGF 320, BGF 160, GFF, and BFF groups, respectively.Conclusions: Using final retrieved vital status data, triple therapy with BGF 320 reduced the risk of death compared with GFF, but was not shown to significantly reduce the risk of death compared with BFF, in patients with COPD. Triple therapy containing a lower dose of inhaled corticosteroid (BGF 160) was not shown to significantly reduce the risk of death compared with the dual therapy comparators.

Persistent airflow limitation can develop in nonsmoking patients with asthma. However, the prevalence and risk factors for airways obstruction with incomplete reversibility in asthma are unknown. We assessed the prevalence of persistent airflow limitation (defined as postbronchodilator FEV(1) or FEV(1)/VC < 75% predicted) in 132 nonsmoking outpatients with severe asthma visiting chest physicians in general hospitals in The Netherlands. They had used inhaled corticosteroids (> or = 1,600 microg/d) and/or daily oral prednisone and long-acting bronchodilators for > 1 yr. In addition, we examined whether persistent airways obstruction in these patients was associated with specific clinical characteristics (age at onset, smoking history, atopic status, bronchodilator reversibility, provocative concentration of histamine causing a 20% decrease in FEV(1) [PC(20)histamine]) or markers of inflammation (exhaled nitric oxide [NO], blood eosinophils, total IgE; and eosinophilia or neutrophilia in induced sputum). Multiple logistic regression analyses were used to calculate adjusted odds ratios (OR). Persistent airflow limitation was observed in 49% of the patients in the study, and apart from older age and longer asthma duration, was strongly associated with a sputum eosinophils percent > or = 2% (OR = 7.7; confidence interval [CI]: 2.4 to 25), PC(20)histamine < or = 1.0 mg/ml (OR = 3.9; CI: 1.2 to 13), and adult onset (> or = 18 yr) of asthma (OR = 3.3; CI: 1.2 to 9). Only sputum eosinophilia appeared to be independently associated with persistent airflow limitation (OR = 8.9; CI: 1.3 to 59). In conclusion, persistent airflow limitation is common in adult patients with severe asthma, and is associated with adult onset of the disease, airway hyperresponsiveness, and most importantly, sputum eosinophilia. These findings suggest that eosinophilic airway inflammation contributes to persistent airflow limitation in severe asthma. Whether reduction of sputum eosinophils with more vigorous treatment leads to a better prognosis in severe asthma is still an open question.

Chronic rhinosinusitis and asthma are conditions that frequently coexist, particularly in severe asthma. The precise mechanism of the relationship between upper and lower airway inflammation is still a matter of debate. We hypothesized that the extent of inflammation in the nasal mucosa is related to lung function and inflammation in the bronchial mucosa in patients with severe asthma.We sought to investigate the relationship between sinonasal inflammation as assessed on computed tomography (CT) scanning, lung function, sputum eosinophilia, and nitric oxide (NO) in exhaled air in patients with severe asthma.Eighty-nine nonsmoking outpatients with severe asthma (29 men and 60 women; mean age 45 years; age range, 18-74 years) were included in this study. CT scans were scored (0-30) by a blinded investigator using a validated method. Lung function, NO in exhaled air, and sputum eosinophils were measured by using standard procedures.CT scans showed abnormalities in 84% of patients. Extensive sinus disease (score 12-30) was found in 24% of patients. There was a significant positive correlation between CT scores and eosinophils in peripheral blood (R(s) = 0.46) and induced sputum (R(s) = 0.40) and level of exhaled NO (R(s) = 0.45, P <.01). CT scores were also positively related to functional residual capacity and inversely related to diffusion capacity, particularly in patients with adult-onset asthma (R(s) = 0.47 and R(s) = -0.53, respectively).The results of this study show a direct relationship between sinonasal mucosa thickness and bronchial inflammation in severe asthma, particularly in patients with adult-onset disease. Whether sinus disease directly affects the intensity of bronchial inflammation is still an unanswered question.

<h3>Study objective</h3> To compare a novel asthma management strategy—budesonide/formoterol in a single inhaler for both maintenance therapy and symptom relief—with a higher dose of budesonide plus as-needed terbutaline. <h3>Methods</h3> This was a 6-month, randomized, double-blind, parallel-group study in patients with mild-to-moderate asthma (n = 697; mean age, 38 years [range, 11 to 79 years]; mean baseline FEV₁, 75% of predicted; mean inhaled corticosteroid [ICS] dosage, 348 μg/d). Following a 2-week run-in period, all patients received two blinded, dry powder inhalers, one containing maintenance medication and one containing medication to be used as needed for the relief of symptoms. Patients were randomized to receive either budesonide/formoterol (80 μg/4.5 μg, two inhalations qd) for maintenance plus additional inhalations as needed for symptom relief, or budesonide (160 μg, two inhalations qd) for maintenance medication plus terbutaline (0.4 mg) as needed. The primary efficacy variable was morning peak expiratory flow (PEF). <h3>Results</h3> Patients receiving budesonide/formoterol showed greater improvements in morning PEF than patients receiving budesonide (increases of 34.5 L/min vs 9.5 L/min, respectively; p < 0.001). The risk of having a severe exacerbation (hospitalization/emergency department [ED] treatment, oral steroids for asthma, or a ≥ 30% decrease from baseline in morning PEF on 2 consecutive days) was 54% lower with budesonide/formoterol vs budesonide (p = 0.0011). Budesonide/formoterol patients experienced 90% fewer hospitalizations/ED treatments due to asthma than budesonide patients (1 vs 10, respectively; p=0.026). The increased efficacy with budesonide/formoterol was achieved with less ICS than was used in the budesonide group (mean dose, 240 μg/d vs 320 μg/d, respectively) and with 77% fewer oral steroid treatment days vs budesonide (114 days vs 498 days, respectively). Both treatments were well tolerated. <h3>Conclusions</h3> Budesonide/formoterol for both maintenance and relief improves asthma control with a lower steroid load compared with a higher dose of budesonide plus terbutaline.

The extended duration of bronchodilation due to formoterol and salmeterol greatly exceeds that of short acting beta 2-adrenoceptor agonists, such as salbutamol or terbutaline. This extended duration and their capacity to "reassert" airway smooth muscle relaxation in vitro despite repeated washing has prompted considerable debate on the underlying mechanism(s). The comparative pharmacology, and molecular modelling of these drugs and of the beta 2-adrenoceptor and its ligand binding core have cast doubt on the exosite/exoceptor model previously proposed to explain the behaviour of salmeterol. We present evidence supporting a unifying hypothesis that the duration of action both of formoterol and salmeterol is determined principally by their physicochemical interactions with membrane lipid bilayers (plasmalemma diffusion microkinetic model), rather than putative distinct exosite/exoceptor binding sites in or near the beta 2-adrenoceptor. This model provides a clearer understanding of the pharmacological profile of these drugs (rate of onset, duration, "reassertion", interaction with hydrophilic and hydrophobic beta 2-adrenoceptor antagonists), and explains why in human airway smooth muscle in vitro a true relaxation-concentration response may not exist for salmeterol.

&lt;i&gt;Background:&lt;/i&gt; Inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are characterized by the presence of eosinophils and neutrophils. However, the mechanisms that mediate the influx of these cells are incompletely understood. Neutrophil products, including neutrophil elastase and antimicrobial peptides such as neutrophil defensins and LL-37, have been demonstrated to display chemotactic activity towards cells from both innate and adaptive immunity. However, chemotactic activity of LL-37 towards eosinophils has not been reported. Therefore, the aim of the present study was to investigate the chemotactic activity of LL-37 for eosinophils and to explore the mechanisms involved in LL-37-mediated attraction of neutrophils and eosinophils. &lt;i&gt;Methods:&lt;/i&gt; Neutrophils and eosinophils were obtained from venous blood of healthy donors. Chemotaxis was studied using a modified Boyden chamber technique. Involvement of formyl-peptide receptors (FPRs) was studied using the antagonistic peptide tBoc-MLP. Activation of the mitogen-activated protein kinase (MAPK) ERK1/2 was studied by Western blotting using antibodies directed against phosphorylated ERK1/2. &lt;i&gt;Results:&lt;/i&gt; Our results show that LL-37 chemoattracts both eosinophils and neutrophils. The FPR antagonistic peptide tBoc-MLP inhibited LL-37-induced chemotaxis. Whereas the FPR agonist fMLP activated ERK1/2 in neutrophils, LL-37 did not, indicating that fMLP and LL-37 deliver different signals through FPRs. &lt;i&gt;Conclusions:&lt;/i&gt; LL-37 displays chemotactic activity for eosinophils and neutrophils, and this activity is mediated via an FPR. These results suggest that LL-37 may play a role in inflammatory lung diseases such as asthma and COPD.

It has been suggested that patients with refractory eosinophilic airway inflammation represent a separate “eosinophilic” asthma phenotype associated with increased morbidity and a poor prognosis. To investigate whether persistent eosinophilia in these patients is a fixed feature or can still be modified by treatment, we investigated the effect of high-dose intramuscular corticosteroids on eosinophils in induced sputum. Twenty-two patients with stable severe asthma (15 women, aged 21–73 years) participated in this double-blind, placebo-controlled study. All were using inhaled corticosteroids (⩾ 1,600 μg/day) or chronic oral prednisone. They were included if the percentage of eosinophils in induced sputum was above the upper limit of normal (⩾ 2%). Two weeks after treatment with triamcinolone, but not placebo, sputum eosinophils almost completely disappeared from a median of 12.6–0.2% (p < 0.001). In 82% of patients, no eosinophils could be observed at all. In addition, the rescue medication score decreased from 1.4 to 0.8 (p = 0.01), and FEV1 improved from a median of 73.8–88.3% predicted (p = 0.001). We conclude that persistent sputum eosinophilia despite extensive antiasthma treatment is not a refractory phenomenon but is still sensitive to high-dose systemic corticosteroids. This implies that these patients with severe asthma need additional or alternative antiinflammatory treatment to combat the eosinophilia and associated poor prognosis.

Interleukin-8 (IL-8; CXCL8) is a cytokine of the CXC chemokine family that is involved in neutrophil recruitment and activation. In addition, IL-8 has been implicated in a wide variety of other processes, including angiogenesis and metastasis in lung cancer. Lung adenocarcinoma and muco-epidermoid carcinoma cells produce substantial amounts of IL-8, and express both CXCR1 and CXCR2 IL-8 receptors. We hypothesized that IL-8 stimulates proliferation of non-small cell lung cancer cells, involving transactivation of the epidermal growth factor receptor (EGFR). The EGFR plays a central role in regulating cell proliferation and it has been therefore implicated in lung cancer. Both EGFR ligands and transactivation of the receptor may lead to downstream signalling events, including mitogen-activated protein kinase (MAPK) activation. Transactivation of the EGFR has been shown to occur in response to ligands of various G-protein coupled receptors (GPCRs) and involves metalloproteinase-mediated release of membrane bound EGFR ligands. The aim of the present study was to investigate the effect of IL-8 on proliferation of lung adenocarcinoma and muco-epidermoid carcinoma cells, and to explore the mechanisms leading to this proliferation in two different non-small cell lung cancer cell lines (A549 and NCI-H292). In both NSCLC cell lines, we observed that IL-8 stimulates epithelial cell proliferation in a dose-dependent manner. The ability of IL-8 to increase cell proliferation was blocked both by an inhibitor of EGFR tyrosine kinase, by a specific anti-EGFR blocking antibody and by a panmetalloproteinase inhibitor. Similar results were obtained using the GPCR inhibitor pertussis toxin. Inhibition of the MAPK p42/44 (ERK1/2) also blocked the mitogenic effect of IL-8, while a p38 MAPK inhibitor did not affect IL-8-induced cell proliferation. These results suggest that IL-8 increases cell proliferation in NSCLC cell lines via transactivation of the EGFR and that this mechanism involves metalloproteinase activity.

Cilomilast (Ariflo), a new oral phosphodiesterase-4 selective inhibitor, improves lung function in chronic obstructive pulmonary disease (COPD). We have evaluated its antiinflammatory effects in 59 patients with COPD randomized to receive cilomilast, 15 mg two times a day, or placebo for 12 weeks. Induced sputum differential cell counts were obtained at baseline and at five further visits. Interleukin-8 and neutrophil elastase were measured in sputum supernatant. Bronchial biopsies obtained at baseline and at Week 10 were immunostained and counted for neutrophils, CD8+ and CD4+ T-lymphocyte subsets, and CD68+ macrophages. Cells expressing the genes for interleukin-8 and tumor necrosis factor-alpha were identified by in situ hybridization and quantified. Compared with placebo, analysis of variance (ANOVA) of the change from baseline showed that cilomilast did not alter any sputum endpoint or FEV1. However, bronchial biopsies demonstrated that cilomilast treatment was associated with reductions in CD8+ (p = 0.001; ANOVA) and CD68+ cells (p < 0.05; ANOVA). In addition, by Poisson analysis, comparison of cell counts analyzed as a ratio of active to placebo demonstrated reductions of CD8+ (48% p < 0.01) and CD68+ (47% p = 0.001) cells. This is the first demonstration of reduction by any agent of airway tissue inflammatory cells characteristic of COPD. Phosphodiesterase-4 inhibitors represent a promising new class of substances for use in antiinflammatory treatment of this disease.

Vorbeugung und Behandlung von Komplikationen, " Reduktion der Mortalität.Die Frühdiagnostik der COPD wird dadurch erschwert, dass Patienten mit leicht-oder sogar mittelgradiger COPD die progrediente Belastungsdyspnoe infolge körperlicher Schonung häufig nicht als störend empfinden und sich daher einer für die Besserung der Prognose möglicherweise wichtigen Frühdiagnostik und frühzeitigen Therapie entziehen.Der Nutzen von lungenfunktionsanalytischen Screening-Untersuchungen in der Allgemeinbevölkerung oder bei Rauchern ist allerdings nicht gesichert.Wesentlich ist bei der Angabe von chronischem (morgendlichem) Husten und/oder Auswurf und/ oder Belastungsdyspnoe sowie bei Vorliegen von Risikofaktoren (l " Tab. 2) die Verdachtsdiagnose ¹COPD" zu stellen und die entsprechende Diagnostik einzuleiten.Bei jedem Schweregrad und in Abhängigkeit von der Komorbidität müssen die Therapieziele individuell und realistisch festgelegt werden.Bei Erstellung eines individuellen Therapieplanes sind Nutzen und Risiken der Behandlungsmaßnahmen für den Betroffenen sowie die direkten und die indirekten Kosten zu beachten.Prinzipiell ist nach erreichter Besserung der Symptomatik für COPD-Patienten eine Reduktion der Therapie zu erwägen.Infolge der typischerweise progredienten Verschlechterung des Befindens und der Lungenfunktion ist allerdings häufig eine Intensivierung der medikamentösen und

Purpose The diagnosis and staging of lung cancer critically depends on surgical procedures. Endoscopic ultrasound (EUS) –guided fine-needle aspiration (FNA) is an accurate, safe, and minimally invasive technique for the analysis of mediastinal lymph nodes (LNs) and can additionally detect tumor invasion (T4) in patients with centrally located tumors. The goal of this study was to assess to what extent EUS-FNA could prevent surgical interventions. Patients and Methods Two hundred forty two consecutive patients with suspected (n = 142) or proven (n = 100) lung cancer and enlarged (&gt; 1 cm) mediastinal LNs at chest computed tomography were scheduled for mediastinoscopy/tomy (94%) or exploratory thoracotomy (6%). Before surgery, all patients underwent EUS-FNA. If EUS-FNA established LN metastases, tumor invasion, or small-cell lung cancer (SCLC), scheduled surgical interventions were cancelled. Surgical-pathologic verification occurred when EUS-FNA did not demonstrate advanced disease. Cancelled surgical interventions because of EUS findings was the primary end point. Results EUS-FNA prevented 70% of scheduled surgical procedures because of the demonstration of LN metastases in non–small-cell lung cancer (52%), tumor invasion (T4) (4%), tumor invasion and LN metastases (5%), SCLC (8%), or benign diagnoses (1%). Sensitivity, specificity, and accuracy for EUS in mediastinal analysis were 91%, 100% and 93%, respectively. No complications were recorded. Conclusion EUS-FNA qualifies as the initial staging procedure of choice for patients with (suspected) lung cancer and enlarged mediastinal LNs. Implementation of EUS-FNA in staging algorithms for lung cancer might reduce the number of surgical staging procedures considerably.

Up to 40% of thoracotomies performed for non-small cell lung cancer are unnecessary, predominantly due to inaccurate preoperative detection of lymph node metastases and mediastinal tumor invasion (T4). Mediastinoscopy and the novel, minimally invasive technique of transesophageal ultrasound-guided fine-needle aspiration (EUS-FNA) target different mediastinal lymph node stations. In addition, EUS can identify tumor invasion in neighboring organs if tumors are located adjacent to the esophagus.To investigate the additional value of EUS-FNA to mediastinoscopy in the preoperative staging of patients with non-small cell lung cancer.Prospective, nonrandomized multicenter trial performed in 1 referral and 5 general hospitals in the Netherlands. During a 3-year period (2000-2003), 107 consecutive patients with potential resectable non-small cell lung cancer underwent preoperative staging by both EUS-FNA and mediastinoscopy. Patients underwent thoracotomy with tumor resection if mediastinoscopy was negative. Surgical-pathological staging was compared with preoperative findings and the added benefit of the combined strategy was assessed.The EUS-FNA examination was performed as an additional staging test to mediastinoscopy in all patients.Detection of mediastinal tumor invasion (T4) and lymph node metastases (N2/N3) comparing the combined staging by both EUS-FNA and mediastinoscopy with staging by mediastinoscopy alone.The combination of EUS-FNA and mediastinoscopy identified more patients with tumor invasion or lymph node metastases (36%; 95% confidence interval [CI], 27%-46%) compared with either mediastinoscopy alone (20%; 95% CI, 13%-29%) or EUS-FNA (28%; 95% CI, 19%-38%) alone. This indicated that 16% of thoracotomies could have been avoided by using EUS-FNA in addition to mediastinoscopy. However, 2% of the EUS-FNA findings were false-positive.These preliminary findings suggest that EUS-FNA, when added to mediastinoscopy, improves the preoperative staging of lung cancer due to the complementary reach of EUS-FNA in detecting mediastinal lymph node metastases and the ability to assess mediastinal tumor invasion.

Background: Inhaled corticosteroids (ICSs) and long-acting β2-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD). Objective: To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD. Design: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847) Setting: 2 university medical centers in The Netherlands. Patients: 114 steroid-naive current or former smokers with moderate to severe COPD. Measurements: Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months. Intervention: Random assignment by minimization method to receive fluticasone propionate, 500 µg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 µg twice daily, and salmeterol, 50 µg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29). Results: 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3+ cells (−55% [95% CI, −74% to −22%]; P = 0.004), CD4+ cells (−78% [CI, −88% to 60%]; P < 0.001), CD8+ cells (−57% [CI, −77% to −18%]; P = 0.010), and mast cells (−38% [CI, −60% to −2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV1 decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3+ cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV1 level. Limitations: The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months. Conclusion: ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects. Primary Funding Source: Netherlands Organization for Scientific Research, Netherlands Asthma Foundation, GlaxoSmithKline of The Netherlands, University Medical Center Groningen, and Leiden University Medical Center.

In spite of the well-demonstrated benefits for patients with COPD, pulmonary rehabilitation programmes show considerable drop-out and suboptimal attendance rates. The purpose of this prospective study is to examine causes for drop-out and non-attendance during a 12 week multidisciplinary pulmonary rehabilitation programme, and to investigate whether sociodemographic and medical factors as well as patients' perception of their illness are related to drop-out and non-attendance.Two hundred and seventeen patients with COPD who were referred to a rehabilitation centre participated in this multicentre study. Prior to treatment, patients received a questionnaire, which included the Illness Perception Questionnaire-Revised. Clinical data were drawn from medical records. Drop-out and attendance were recorded during the programme.Fifty patients (23%) did not complete the rehabilitation course, of which half was due to medical reasons (e.g. exacerbations, hospitalisations). Non-completion could not be predicted by baseline sociodemographic, clinical or psychological variables. Patients who declined treatment did not differ from patients who dropped out due to medical reasons. On average, patients attended 92% of all scheduled appointments. Of all missed appointments, approximately 20% were accountable to factors beyond patients' control (e.g. absent therapists, hospitalisations). Smoking, living alone, a lower fat free mass and lower confidence in treatment increased the chance of patients not attending an appointment during rehabilitation.In general, adherence in rehabilitation is high. However, paying attention to patients' nutritional status and creating a positive expectation of treatment during referral and intake appear to be important if one aims to optimise patients' attendance during rehabilitation.

Endobronchial Ultrasound Guided Transbronchial Needle Aspiration (EBUS-TBNA) and Trans-esophageal Ultrasound Scanning with Fine Needle Aspiration (EUS-FNA) are important, novel techniques for the diagnosis and staging of non-small cell lung cancer (NSCLC) that have been incorporated into lung cancer staging guidelines. To guide and optimize treatment decisions, especially for NSCLC patients in stage III and IV, EGFR and KRAS mutation status is often required. The concordance rate of the mutation analysis between these cytological aspirates and histological samples obtained by surgical staging is unknown. Therefore, we studied the extent to which allele-specific quantitative real-time PCR with hydrolysis probes could be reliably performed on EBUS and EUS fine needle aspirates by comparing the results with histological material from the same patient. We analyzed a series of 43 NSCLC patients for whom cytological and histological material was available. We demonstrated that these standard molecular techniques can be accurately applied on fine needle cytological aspirates from NSCLC patients. Importantly, we show that all mutations detected in the histological material of primary tumor were also identified in the cytological samples. We conclude that molecular profiling can be reliably performed on fine needle cytology aspirates from NSCLC patients.

Background: Asthma and obesity are associated disorders, but the contribution of obesity to difficult‐to‐treat asthma as well as the mechanisms responsible for this relationship are unclear. The aim of this study was to investigate the relationship between obesity (body mass index ≥ 30) and factors related with asthma severity in patients with difficult‐to‐treat asthma. Methods: One hundred and thirty‐six nonsmoking asthmatic adults with persistent symptoms despite high doses of inhaled or oral corticosteroids and long‐acting bronchodilators were studied [70% female, median (range) age 44.6 (18–75) years, 32% on daily oral corticosteroids]. The association between obesity, lung function parameters [forced expiratory volume in 1 s (FEV 1 ), functional residual capacity/total lung capacity (FRC/TLC)], inflammatory markers [blood eosinophils, sputum eosinophils and neutrophils, exhaled nitric oxide (FE NO ), airway hyperresponsiveness, C‐reactive protein (CRP)] and aggravating co‐morbid factors (severe chronic sinus disease, gastro‐esophageal reflux, recurrent respiratory infections, psychopathology and obstructive sleep apnea) was investigated. Results: Obese patients ( n = 29) had a higher FEV 1 %pred ( P = 0.05) and a lower FRC/TLC%pred ( P &lt; 0.01) compared with nonobese patients ( n = 107). Body mass index was inversely related with sputum eosinophils ( r = −0.36, P &lt; 0.01) and FE NO ( r = −0.30, P &lt; 0.01). Obese patients had an increased risk for gastro‐esophageal reflux (OR = 2.3) and sleep apnea (OR = 3.1). Conclusion: Obesity in patients with difficult‐to‐treat asthma is inversely related with sputum eosinophils and FE NO , and positively associated with the presence of co‐morbid factors and reduced lung volumes. This suggests that other factors than airway inflammation alone explain the relationship between obesity and asthma severity.

The recent development of new β2-adrenoceptor agonists with a duration of action in excess of 12 h may change strategies in the treatment of bronchial asthma. This study aims at the direct comparison of the main representatives of this new class of drugs, formoterol (F) and salmeterol (S), in asthmatic patients over the course of 24 h. Twelve patients with mild bronchial asthma participated in a double-blind, randomized, placebo-controlled clinical trial. In a dose-finding study we determined the protective and bronchodilating effects of 12 and 24 µg F aerosol vs 50 and 100 µg S 30 min after inhalation. In a 24-h study we investigated the effects of 12 µg F and 50 µg S on airway tone and responsiveness. Bronchial responsiveness was assessed as the dose of methacholine necessary to decrease FEV1 by 20%. In the dose-finding study, compared with placebo, all doses of F and S equally increased FEV1 (p < 0.003) and protected against inhaled methacholine (p < 0.0001). In the 24-h study 12 µg F and 50 µg S increased FEV1 and significantly protected against methacholine-induced bronchoconstriction up to 24 h (p < 0.05), compared with placebo. Phase and amplitude of the circadian variation of FEV1 and airway responsiveness were not affected. Clinically recommended doses of aerosolized F (12 µg) and S (50 µg) have a duration of action up to 24 h and are equally effective at bronchodilation and protection in acute experiments in patients with mild bronchial asthma.

The involvement of small airways in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD) has been debated for a long time. However, a proper definition of small airway disease is still lacking, and neither a widely accepted biomarker nor a functional parameter to assess small airway abnormalities and to explore the effect of tested compounds on small airways is available. Aiming towards increased knowledge and consensus on this topic, this perspective paper intends to (i) strengthen awareness among the scientific community on the role of small airways in asthma and COPD; (ii) examine the pros and cons of some biological, functional and imaging parameters in the assessment of small airway abnormalities; and (iii) discuss the evidence for distal airway pharmacological targeting in asthma and COPD.

Background Obtaining a tissue diagnosis of malignancy is challenging in patients with suspected lung cancer presenting with centrally located intrapulmonary masses. Objective (1) To evaluate the yield of endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS-TBNA) for diagnosing centrally located lesions after a non-diagnostic conventional bronchoscopy. (2) To assess the impact of EBUS-TBNA on patient management for this indication. Study design and patients A retrospective analysis of a series of patients with a central parenchymal lung lesion suspected to be lung cancer who had been referred to three university hospitals for EBUS-TBNA to obtain a tissue diagnosis was undertaken. If EBUS-TBNA did not result in a formal pathological diagnosis of malignancy, patients were subsequently referred for a transthoracic needle aspiration biopsy or a surgical diagnostic procedure. Results Sixty patients were investigated with EBUS-TBNA. The majority (82%) had a prior (non-diagnostic) flexible bronchoscopy. EBUS-TBNA was performed in an out-patient setting in 97%. With ultrasound, the primary lung lesion was observed in all cases. EBUS-TBNA confirmed lung cancer in 46 (77%). A final reference pathology diagnosis was available in 59 (98%) cases. The sensitivity of EBUS-TBNA for diagnosing lung cancer was 82% (95% confidence intervals (CI) 69–91%) with a negative predictive value of 23% (95%CI 5–53%). Based on the EBUS-TBNA findings, transthoracic needle aspiration biopsy or a surgical diagnostic procedure was cancelled in 47% and 30% of patients, respectively. No serious procedure-related complications were reported. Conclusion EBUS-TBNA is a sensitive tool for the diagnosis of centrally located primary lung cancer not visible at conventional bronchoscopy. Therefore, EBUS-TBNA can impact on patient management in this setting. However, the low negative predictive value indicates that a negative EBUS-TBNA result should be confirmed by other methods. Implication EBUS-TBNA can be considered as a diagnostic test in patients with a centrally located lung lesion after a previous non-diagnostic conventional bronchoscopy.

Bronchial biopsy specimens from chronic obstructive pulmonary disease (COPD) patients demonstrate increased numbers of CD8+ T-lymphocytes, macrophages and, in some studies, neutrophils and eosinophils. Smoking cessation affects the rate of forced expiratory volume in one second (FEV(1)) decline in COPD, but the effect on inflammation is uncertain. Bronchial biopsy inflammatory cell counts were compared in current and ex-smokers with COPD. A pooled analysis of subepithelial inflammatory cell count data from three bronchial biopsy studies that included COPD patients who were either current or ex-smokers was performed. Cell count data from 101 subjects, 65 current smokers and 36 ex-smokers, were analysed for the following cell types: CD4+ and CD8+ T-lymphocytes, CD68+ (monocytes/macrophages), neutrophil elastase+ (neutrophils), EG2+ (eosinophils), mast cell tryptase+ and cells mRNA-positive for tumour necrosis factor-alpha. Current smokers and ex-smokers were similar in terms of lung function, as measured by FEV(1) (% predicted), forced vital capacity (FVC) and FEV(1)/FVC. The results demonstrate that there were no significant differences between smokers and ex-smokers in the numbers of any of the inflammatory cell types or markers analysed. It is concluded that, in established chronic obstructive pulmonary disease, the bronchial mucosal inflammatory cell infiltrate is similar in ex-smokers and those that continue to smoke.

The cyclic nucleotide phosphodiesterase (PDE) of guinea‐pig eosinophils was partially characterized and the effects of selective inhibitors of PDE isoenzymes upon opsonized zymosan (OZ)‐stimulated respiratory burst were studied. PDE activity in eosinophil lysates appeared to be membrane‐associated, displayed substrate specificity for adenosine 3′: 5′ cyclic monophosphate (cyclic AMP) versus guanosine 3′: 5′ cyclic monophosphate (cyclic GMP) and was insensitive to cyclic GMP or Ca 2+ and calmodulin. The non‐selective PDE inhibitor, 3‐isobutyl‐1‐methylxanthine caused a concentration‐dependent inhibition of both OZ‐stimulated hydrogen peroxide (H 2 O 2 ) generation and cyclic AMP hydrolysis. The type IV‐selective PDE inhibitors, rolipram and denbufylline, also inhibited H 2 O 2 generation and cyclic AMP hydrolysis in a concentration‐dependent manner whilst SK&amp;F 94120 and Org 9935 (type III‐selective) and zaprinast (type Ia or V‐selective) were ineffective. Dibutyryl cyclic AMP, a cell‐permeable, non‐hydrolysable analogue of cyclic AMP, caused a concentration‐dependent inhibition of H 2 O 2 generation stimulated by OZ. Dibutyryl cyclic GMP was ineffective. It is concluded that eosinophil respiratory burst activity induced by OZ can be regulated by intracellular cyclic AMP and that the levels of cyclic AMP are controlled exclusively by a rolipram‐ and denbufylline‐sensitive PDE isoenzyme that resembles a type IV species.

The physician's global evaluation of treatment effectiveness (GETE) at 16 weeks has been shown to be the most effective assessment of response to omalizumab (XOLAIR®). This randomized, open-label, parallel-group study evaluated the persistency of treatment responder classification in patients receiving omalizumab added to optimized asthma therapy (OAT).Patients (12-75 years, n = 400) with severe allergic asthma, uncontrolled despite Global Initiative for Asthma 2004 Step 4 therapy, received OAT and omalizumab (n = 272) or OAT (n = 128) for 32 weeks. Response or nonresponse was evaluated at Weeks 16 and 32. Response was defined as an investigator's (physician's) GETE rating of excellent or good; nonresponse was defined as a rating of moderate, poor or worsening.Three hundred and forty-nine patients had GETE ratings available at Weeks 16 and 32 (omalizumab n = 258, OAT n = 91). Omalizumab responders of about 171/187 (91.4%)and 44/71 (62.0%) omalizumab nonresponders at Week 16 persisted as responders or nonresponders at Week 32. The investigator's GETE at Week 16 predicted persistency of response or nonresponse to omalizumab at Week 32 for 83.3% (215/258) of patients. OAT patients showed a lower persistency of response (18/28 [64.3%]) and a higher persistency of nonresponse (57/63 [90.5%]) than omalizumab patients. Excellent and good GETE ratings in omalizumab-treated patients were reflected by improvements in exacerbation rates (P < 0.001), severe exacerbation rates (P = 0.023), hospitalizations (P = 0.003), total emergency visits (P = 0.026) and Asthma Control Questionnaire overall score (P < 0.001).Response to omalizumab, as assessed by a physician's GETE at 16 weeks, is an effective predictor of continuing persistent response to omalizumab for the majority of patients.

A tissue diagnosis of mediastinal nodes is frequently needed for accurate lung cancer staging as well as the assessment of mediastinal masses. Transbronchial needle aspiration (TBNA) is a safe procedure that is performed during routine bronchoscopy. Provided mediastinal metastases are confirmed, TBNA has a high impact on patient management. Unfortunately, TBNA remains underused in current daily practice, mainly due to the lack of real-time needle visualisation. The introduction of echo-endoscopes has overcome this problem. Endobronchial ultrasound-guided TBNA (EBUS-TBNA) allows real-time controlled tissue sampling of paratracheal, subcarinal and hilar lymph nodes. Mediastinal lymph nodes located adjacent to the oesophagus can be assessed by transoesophageal ultrasound-guided fine needle aspiration (EUS-FNA). Owing to the complementary reach of EBUS-TBNA and EUS-FNA in assessing different regions of the mediastinum, recent studies suggest that complete and accurate mediastinal staging can be achieved by the combination of both procedures. It is expected that implementation of minimally invasive endoscopic methods of endobronchial ultrasound-guided transbronchial needle aspiration and transoesophageal ultrasound-guided fine needle aspiration will reduce the need for surgical staging of lung cancer significantly.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) research statement is to describe evidence related to diagnosis, assessment and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS research statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centred outcomes.

According to international treatment guidelines, inhaled rapid-acting β2 agonists should be used for the control of symptoms in patients with asthma. We compared the efficacy and safety of an extrafine combination inhaler containing a corticosteroid (beclometasone) plus a rapid-onset, long-acting β2 agonist (formoterol) with a short-acting β2 agonist (salbutamol) as reliever strategies in patients taking beclometasone-formoterol combination as maintenance treatment.In a double-blind trial undertaken in 183 centres in 14 European countries over 48 weeks, patients (aged ≥18 years) with asthma that was not fully controlled, with a forced expiratory volume in 1 s (FEV1) of at least 60% predicted, had a 2-week run in. During this period, patients were treated with a combination of beclometasone 100 μg and formoterol 6 μg per one inhalation twice daily plus salbutamol 100 μg as required delivered by use of a pressurised metered-dose inhaler. They were then randomly assigned in a 1:1 ratio with a computer-generated randomisation list to receive beclometasone 100 μg plus formoterol 6 μg or salbutamol 100 μg as reliever in addition to maintenance with beclometasone 100 μg plus formoterol 6 μg twice daily. Primary outcome was the time to first severe exacerbation (admission to hospital or visit to emergency department, or use of systemic steroids for ≥3 consecutive days). Secondary outcomes were number of severe exacerbations (events per 100 patients per year), time to and number of mild exacerbations, additional exacerbation variables, lung function, symptom scores, and asthma control. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00861926.1714 patients were randomly assigned to the as-needed beclometasone-formoterol (n=857) and as-needed salbutamol groups (n=857), and 1701 were analysed (852 and 849, respectively). 326 severe exacerbations were reported by 251 patients during the study, and 99 versus 152 patients had at least one exacerbation during the 48 weeks, respectively. Compared with beclometasone-formoterol plus salbutamol as needed, beclometasone-formoterol for both maintenance and reliever treatment significantly increased the time to first exacerbation (209 days vs 134 days) by 75 days, with a 36% reduction in risk (hazard ratio 0·64 [95% CI 0·49 to 0·82]; p=0·0005), and the estimated probability was 12% and 18%, respectively (p=0·0003). The number of days with mild asthma exacerbations was also lower with as-needed beclometasone-formoterol than with as-needed salbutamol (56·04 days per patient per year vs 65·11 days per patient per year; 0·86 [0·76 to 0·98]; p=0·021). From the run-in period to week 48, both treatments improved symptoms (mean change -1·59 [-1·94 to -1·25] in the as-needed beclometasone-formoterol group vs -1·44 [-1·78 to -1·10] in the as-needed salbutamol group, difference -0·15 [-0·60 to 0·30]; p=0·507), percentage of asthma control days (9·5% [7·3 to 11·8] vs 10·9% [8·7 to 13·1], respectively, -1·4 [-4·3 to 1·6]; p=0·359), use of reliever (-0·29 [-0·38 to -0·20] vs -0·27 [-0·36 to -0·19], respectively, -0·02 [-0·13 to 0·10]; p=0·794), and lung function (FEV1, 0·090 [0·060 to 0·120] vs 0·090 [0·060-0·120], respectively, 0·001 [-0·040 to 0·040]; p=0·969), and were well tolerated (patients with serious adverse events, 32 [4%] and 41 [5%], respectively).Our results lend support to the use of the combination of a single inhaled corticosteroid plus a rapid-onset, long-acting β2 agonist for maintenance and relief in patients with moderate to severe asthma and provide encouraging data for the formulation of beclometasone-formoterol for this use.Chiesi Farmaceutici.

The 2008-2013 World Health Organization (WHO) action plan on noncommunicable diseases (NCDs) includes chronic respiratory diseases as one of its four priorities. Major chronic respiratory diseases (CRDs) include asthma and rhinitis, chronic obstructive pulmonary disease, occupational lung diseases, sleep-disordered breathing, pulmonary hypertension, bronchiectiasis and pulmonary interstitial diseases. A billion people suffer from chronic respiratory diseases, the majority being in developing countries. CRDs have major adverse effects on the life and disability of patients. Effective intervention plans can prevent and control CRDs, thus reducing morbidity and mortality. A prioritised research agenda should encapsulate all of these considerations in the frame of the global fight against NCDs. This requires both CRD-targeted interventions and transverse NCD programmes which include CRDs, with emphasis on health promotion and disease prevention.

This document is a revision of the guideline for diagnosis and treatment of COPD that replaces the version from 2007. A multitude of recent reports regarding risk factors, diagnosis, assessment, prevention and pharmacological as well as non-pharmacological treatment options made a major revision mandatory. The new guideline is based on the GOLD document taking into account specifics in Germany and Austria.Das vorliegende Dokument ist eine Neufassung und Aktualisierung der Leitlinie zur Diagnostik und Therapie von Patienten mit COPD, die die bisherige Version aus dem Jahr 2007 ablöst. Die Fülle an neuen Erkenntnissen zu Risikofaktoren, Diagnostik, Schweregradeinschätzung, Prävention und medikamentösen sowie nicht medikamentösen Therapiemaßnahmen machten eine umfassende Überarbeitung erforderlich. Die neue Leitlinie baut auf das GOLD-Dokument unter Berücksichtigung von Besonderheiten in Deutschland und Österreich auf.

This document provides clinical recommendations for the prevention of chronic obstructive pulmonary disease (COPD) exacerbations. It represents a collaborative effort between the European Respiratory Society and the American Thoracic Society. Comprehensive evidence syntheses were performed to summarise all available evidence relevant to the Task Force9s questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of COPD experts. After considering the balance of desirable (benefits) and undesirable consequences (burden in the form of adverse effects and cost), quality of evidence, feasibility, and acceptability of various interventions, the Task Force made recommendations for mucolytic, long-acting muscarinic antagonist, phosphodiesterase-4 inhibitor (roflumilast) and macrolide therapy, as well as a conditional recommendation against fluoroquinolone therapy. All of the recommendations were conditional, except for a strong recommendation for the use of a long-acting antimuscarinic agent <i>versus</i> a long-acting β₂-adrenergic, indicating that there was uncertainty about the balance of desirable and undesirable consequences of the intervention, and that well-informed patients may make different choices regarding whether to have or not have the specific intervention. The guideline summarises the evidence and provides recommendations for pharmacological therapy for the prevention of COPD exacerbations.

BackgroundThe German COPD cohort study COSYCONET (“COPD and SYstemic consequences-COmorbidities NETwork”) investigates the interaction of lung disease, comorbidities and systemic inflammation. Recruitment took place from 2010 to 2013 in 31 study centers. In addition to the baseline visit, follow-up visits are scheduled at 6, 18, 36 and 54 months after baseline. The study also comprises a biobank, image bank, and includes health economic data. Here we describe the study design of COSYCONET and present baseline data of our COPD cohort.MethodsInclusion criteria were broad in order to cover a wide range of patterns of the disease. In each visit, patients undergo a large panel of assessments including e.g. clinical history, spirometry, body plethysmography, diffusing capacity, blood samples, 6-min walk-distance, electrocardiogram and echocardiography. Chest CTs are collected if available and CTs and MRIs are performed in a subcohort. Data are entered into eCRFs and subjected to several stages of quality control.ResultsOverall, 2741 subjects with a clinical diagnosis of COPD were included (59% male; mean age 65 ± 8.6 years (range 40–90)). Of these, 8/35/32/9% presented with GOLD stages I–IV; 16% were uncategorized, including the former GOLD-0 category. 24% were active smokers, 68% ex-smokers and 8% never-smokers. Data completeness was 96% for the baseline items.ConclusionThe German COPD cohort comprises patients with advanced and less advanced COPD. This is particularly useful for studying the time course of COPD in relation to comorbidities. Baseline data indicate that COSYCONET offers the opportunity to investigate our research questions in a large-scale, high-quality dataset.

The oral, selective phosphodiesterase type-4 inhibitor roflumilast reduces exacerbations and improves lung function in patients with severe-to-very severe chronic obstructive pulmonary disease (COPD). We investigated the efficacy and safety of roflumilast used concomitantly with long-acting β(2)-agonists (LABAs) to reduce exacerbations, and the influence of exacerbation history. Pooled data were analysed from two 12-month, placebo-controlled roflumilast (500 μg once daily) studies involving 3,091 patients with severe-to-very severe COPD. Approximately half of patients used concomitant LABAs; 39% used concomitant short-acting muscarinic antagonists (SAMAs); 27% were frequent exacerbators (two or more exacerbations per year). Roflumilast reduced the rate of moderate or severe exacerbations, with LABA (rate ratio (RR) 0.79, 95% CI 0.69-0.91; p=0.001) or without LABA (RR 0.85, 95% CI 0.74-0.99; p=0.039) and prolonged time both to first (p=0.035 with LABA, p=0.300 without LABA) and second (p=0.018 with LABA, p=0.049 without LABA) exacerbations. Frequent exacerbators experienced a reduction in moderate or severe exacerbations (RR 0.78, 95% CI 0.66-0.91; p=0.002). Similarly, roflumilast remained effective with concomitant SAMA. No differences arose in adverse events between these subgroups. Roflumilast may be used to reduce exacerbations and improve dyspnoea and lung function, without increasing adverse events in COPD patients receiving concomitant LABAs.

Extracellular matrix (ECM) composition has an important role in determining airway structure. We postulated that ECM lung composition of chronic obstructive pulmonary disease (COPD) patients differs from that observed in smoking and nonsmoking subjects without airflow obstruction. We determined the fractional areas of elastic fibres, type-I, -III and -IV collagen, versican, decorin, biglycan, lumican, fibronectin and tenascin in different compartments of the large and small airways and lung parenchyma in 26 COPD patients, 26 smokers without COPD and 16 nonsmoking control subjects. The fractional area of elastic fibres was higher in non-obstructed smokers than in COPD and nonsmoking controls, in all lung compartments. Type-I collagen fractional area was lower in the large and small airways of COPD patients and in the small airways of non-obstructed smokers than in nonsmokers. Compared with nonsmokers, COPD patients had lower versican fractional area in the parenchyma, higher fibronectin fractional area in small airways and higher tenascin fractional area in large and small airways compartments. In COPD patients, significant correlations were found between elastic fibres and fibronectin and lung function parameters. Alterations of the major ECM components are widespread in all lung compartments of patients with COPD and may contribute to persistent airflow obstruction.

Pulmonary disease (PD) caused by Mycobacterium avium complex (MAC) is increasing worldwide. We conducted a systematic review of studies that include microbiologic outcomes to evaluate current macrolide-based treatment regimens.We searched literature published before April 2017 by using the MEDLINE, Cochrane, and Embase databases. Risk of bias in randomized trials was assessed using the Cochrane tool.We retrieved 333 citations and evaluated 42 studies including 2,748 patients: 18 studies were retrospective chart reviews, 18 were prospective, and six were randomized. The weighted average proportion of sputum culture conversions in macrolide-containing regimens after subtracting posttreatment microbiologic recurrences was 52.3% (95% CI, 44.7%-59.9%). Using the triple-drug regimens recommended by the American Thoracic Society (ATS) achieved treatment success in 61.4% (95% CI, 49.7%-72.5%), which further increased to 65.7% (95% CI, 53.3%-77.4%) when drugs were taken for at least 1 year by patients who were macrolide susceptible and had previously untreated MAC. The overall risk of bias was low in five of the six randomized trials. However, selective outcome reporting because of a posteriori exclusion of initially included patients (14.0%), uncompleted treatment (17.6%), and inconsistent use of outcome parameters (17 definitions of treatment success) hampered the comparison of nonrandomized trials.To date, randomized studies on treatment outcome in patients with MAC PD are scarce. Long-term treatments with ATS-recommended regimens for patients who are macrolide susceptible are superior to other macrolide-based therapies. A standardized definition of treatment success and genotypic distinction between reinfection and relapse by means of pretreatment and posttreatment identification of MAC species in cases of microbiologic recurrences may help to optimize evaluation of treatment regimens in the future.

In the past, asthma was considered mainly as a childhood disease. However, asthma is an important cause of morbidity and mortality in the elderly nowadays. In addition, the burden of asthma is more significant in the elderly than in their younger counterparts, particularly with regard to mortality, hospitalization, medical costs or health-related quality of life. Nevertheless, asthma in the elderly is still been underdiagnosed and undertreated. Therefore, it is an imperative task to recognize our current challenges and to set future directions. This project aims to review the current literature and identify unmet needs in the fields of research and practice for asthma in the elderly. This will enable us to find new research directions, propose new therapeutic strategies, and ultimately improve outcomes for elderly people with asthma. There are data to suggest that asthma in older adults is phenotypically different from young patients, with potential impact on the diagnosis, assessment and management in this population. The diagnosis of AIE in older populations relies on the same clinical findings and diagnostic tests used in younger populations, but the interpretation of the clinical data is more difficult. The challenge today is to encourage new research in AIE but to use the existing knowledge we have to make the diagnosis of AIE, educate the patient, develop a therapeutic approach to control the disease, and ultimately provide a better quality of life to our elderly patients.

Rationale: Moderate and severe exacerbations are incompletely prevented by maximal inhalation therapy in patients with severe chronic obstructive pulmonary disease.Objectives: To determine whether roflumilast reduces moderate and/or severe chronic obstructive pulmonary disease exacerbations in patients at risk for exacerbations despite treatment with inhaled corticosteroid/long-acting β2-agonist with or without a long-acting muscarinic antagonist (LAMA).Methods: In this 52-week, phase 4, double-blind, placebo-controlled RE2SPOND (Roflumilast Effect on Exacerbations in Patients on Dual [LABA/ICS] Therapy) trial (NCT01443845), participants aged 40 years or older with severe/very severe chronic obstructive pulmonary disease, chronic bronchitis, two or more exacerbations and/or hospitalizations in the previous year, and receiving inhaled corticosteroid/long-acting β2-agonist with or without LAMA daily for 3 or more months were equally randomized to once-daily roflumilast, 500 μg (n = 1,178), or placebo (n = 1,176). Stratification was based on LAMA use.Measurements and Main Results: Although rate of moderate or severe exacerbations per patient per year (primary endpoint) was reduced by 8.5% with roflumilast versus placebo, the between-group difference was not statistically significant (rate ratio, 0.92; 95% confidence interval, 0.81–1.04; P = 0.163). However, roflumilast improved lung function, and in a post hoc analysis roflumilast significantly reduced the rate of moderate or severe exacerbations in participants with a history of more than three exacerbations and/or one or more hospitalizations in the prior year. Adverse event–related discontinuations occurred in 11.7% roflumilast-treated and 5.4% placebo-treated participants. Deaths occurred in 2.5% roflumilast and 2.1% placebo participants.Conclusions: Roflumilast failed to statistically significantly reduce moderate and/or severe exacerbations in the overall population. Roflumilast improved lung function and reduced exacerbations in participants with frequent exacerbations and/or hospitalization history. The safety profile of roflumilast was consistent with that of previous studies.Clinical trial registered with www.clinicaltrials.gov (NCT01443845).

Background COPD exacerbations are associated with increased morbidity and mortality and can accelerate disease progression. The best predictor of future exacerbations is a history of previous exacerbations, which helps identify a frequent exacerbator phenotype. This post hoc analysis evaluated the effect of roflumilast, a drug known to reduce the COPD exacerbation rate, on exacerbation status. Methods Pooled data from two 1-year, placebo-controlled, roflumilast (500 μg once daily) studies in patients with symptomatic COPD and severe airflow obstruction were evaluated (studies M2-124 and M2-125, ClinicalTrials.gov identifiers NCT00297102 and NCT00297115). A total of 3,091 patients were included in this analysis (62.5% with GOLD [Global Initiative for Chronic Obstructive Lung Disease] III COPD and 29.2% with GOLD 4 COPD). Based on their exacerbation frequency status in the previous year, patients were classified as frequent (two or more events) or infrequent (fewer than two events) exacerbators. Exacerbation frequency was analyzed at baseline and at year 1. Results Among frequent exacerbators treated with roflumilast, 32.0% still had frequent exacerbations at year 1 compared with 40.8% of placebo-treated patients (risk ratio, 0.799; P = .0148). Among infrequent exacerbators, 17.5% of roflumilast-treated patients became frequent exacerbators at year 1 compared with 22.9% of those taking placebo (risk ratio, 0.768; P = .0018). The reduction in severe exacerbations leading to hospitalization/death was similar between subgroups and occurred independently of concomitant long-acting β2-agonists or previous inhaled corticosteroid treatment. When analyzed by severity of airflow limitation, 26.4% of roflumilast-treated frequent exacerbators with GOLD III COPD remained frequent exacerbators at year 1 compared with 38.9% of those taking placebo (P = .0042). Conclusions Treatment with roflumilast shifts patients from the frequent to the more stable infrequent exacerbator state. Trial registry ClinicalTrials.gov; No.: NCT00297102 and NCT00297115; URL: www.clinicaltrials.gov COPD exacerbations are associated with increased morbidity and mortality and can accelerate disease progression. The best predictor of future exacerbations is a history of previous exacerbations, which helps identify a frequent exacerbator phenotype. This post hoc analysis evaluated the effect of roflumilast, a drug known to reduce the COPD exacerbation rate, on exacerbation status. Pooled data from two 1-year, placebo-controlled, roflumilast (500 μg once daily) studies in patients with symptomatic COPD and severe airflow obstruction were evaluated (studies M2-124 and M2-125, ClinicalTrials.gov identifiers NCT00297102 and NCT00297115). A total of 3,091 patients were included in this analysis (62.5% with GOLD [Global Initiative for Chronic Obstructive Lung Disease] III COPD and 29.2% with GOLD 4 COPD). Based on their exacerbation frequency status in the previous year, patients were classified as frequent (two or more events) or infrequent (fewer than two events) exacerbators. Exacerbation frequency was analyzed at baseline and at year 1. Among frequent exacerbators treated with roflumilast, 32.0% still had frequent exacerbations at year 1 compared with 40.8% of placebo-treated patients (risk ratio, 0.799; P = .0148). Among infrequent exacerbators, 17.5% of roflumilast-treated patients became frequent exacerbators at year 1 compared with 22.9% of those taking placebo (risk ratio, 0.768; P = .0018). The reduction in severe exacerbations leading to hospitalization/death was similar between subgroups and occurred independently of concomitant long-acting β2-agonists or previous inhaled corticosteroid treatment. When analyzed by severity of airflow limitation, 26.4% of roflumilast-treated frequent exacerbators with GOLD III COPD remained frequent exacerbators at year 1 compared with 38.9% of those taking placebo (P = .0042). Treatment with roflumilast shifts patients from the frequent to the more stable infrequent exacerbator state.

The objective of this study was to estimate the burden of disease in incident patients with non-tuberculous mycobacterial pulmonary disease (NTM-PD). A sample of 7 073 357 anonymised persons covered by German public statutory health insurances was used to identify patients with NTM-PD. In total, 125 patients with newly diagnosed NTM-PD in 2010 and 2011 were matched with 1250 control patients by age, sex and Charlson Comorbidity Index, and followed for 39 months. The incidence rate for NTM-PD was 2.6 per 100 000 insured persons (95% CI 2.2–3.1). The mortality rate for patients with NTM-PD and the control group in the observational period was 22.4% and 6%, respectively (p&lt;0.001). Mean direct expenditure per NTM-PD patient was €39 559.60 (95% CI 26 916.49–52 202.71), nearly 4-fold (3.95, 95% CI 3.73–4.19) that for a matched control (€10 006.71, 95% CI 8907.24–11 106.17). Hospitalisations were three times higher in the NTM-PD group and accounted for 63% of the total costs. Attributable annual direct costs and indirect work-loss costs in NTM-PD patients were €9093.20 and €1221.05 per control patient, respectively. Only 74% of NTM-PD patients received antibiotics and nearly 12% were prescribed macrolide monotherapy. Although NTM-PD is considered rare, the attributable mortality and financial burden in Germany are high. Efforts to heighten awareness of appropriate therapy are urgently needed.

Pirfenidone is currently approved in the EU for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) and offers a beneficial risk-benefit profile. However, there are several other, progressive fibrotic lung diseases, in which conventional anti-inflammatory therapy is not sufficiently effective and antifibrotic therapies may offer a novel treatment option.We designed a study protocol for inclusion of patients with progressive fibrotic lung disease despite conventional anti-inflammatory therapy (EudraCT 2014-000861-32). The study population comprises patients with collagen-vascular disease-associated lung fibrosis (CVD-LF), fibrotic non-specific interstitial pneumonia (fNSIP), chronic hypersensitivity pneumonitis (cHP), and asbestos-related lung fibrosis (ALF). Disease progression needs to be proven by slope calculation of at least three Forced Vital Capacity (FVC) values obtained within 6-24 months prior to inclusion, documenting an annualized decline in percent predicted FVC of 5% (absolute) or more despite appropriate conventional therapy. Absolute change in percent predicted FVC from baseline - analyzed using a rank analysis of covariance (ANCOVA) model - will serve as efficacy-related primary study endpoint.There is an urgent unmet clinical need for effective therapies for patients with a progressive fibrotic lung disease other than IPF. The current study protocol is unique with respect to selecting patients with different disease entities of lung fibrosis which have, however, essential pathophysiological characteristics in common. Moreover, by selecting patients with evidence of disease progression despite conventional therapy, the protocol ensures that a cohort of interstitial lung disease (ILD) patients with a high unmet medical need is targeted and it may allow a sufficiently high event rate for evaluation of treatment responses.DRKS00009822 (registration date: January 13th 2016).

The phosphodiesterase 4 inhibitor roflumilast is a first-in-class antiinflammatory treatment for severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and a history of frequent exacerbations. In previous clinical studies, a transient and reversible weight decrease was reported with roflumilast, suggesting the systemic actions of this drug may impact metabolism. Our objective was to investigate the effects of roflumilast on glucose homeostasis and body weight. We conducted a 12-wk, randomized, double-blind, placebo-controlled multicenter study with outpatients. Patients (n = 205) with newly diagnosed type 2 diabetes mellitus (DM2) but without COPD were included in the study. Roflumilast 500 μg or placebo was administered once daily. We evaluated mean change in blood glycated hemoglobin levels. We also evaluated mean change from baseline in the postmeal area under the curve (AUC) for a range of metabolic parameters. Roflumilast was associated with a significantly greater reduction in glycated hemoglobin levels than placebo (least square mean = −0.45%; P < 0.0001) in patients with DM2. In the roflumilast group, postmeal AUC decreased significantly from baseline to last visit for free fatty acids, glycerol, glucose, and glucagon, whereas they slightly increased for C-peptide and insulin. In contrast to roflumilast, the glucagon AUC increased with placebo, and the insulin AUC decreased. Between-treatment analysis revealed statistically significant differences in favor of roflumilast for glucose (P = 0.0082), glycerol (P = 0.0104), and C-peptide levels (P = 0.0033). Patients in both treatment groups lost weight, although the between-treatment difference of the changes from baseline to last visit [−0.7 (0.4) kg] was not statistically significant (P = 0.0584). Roflumilast lowered glucose levels in patients with newly diagnosed DM2 without COPD, suggesting positive effects on glucose homoeostasis.

BackgroundLong-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone. The Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-1) (NCT01854645) and the Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-2) (NCT01854658) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [FF] 18/9.6-μg (GFF) metered dose inhaler (MDI) formulated using the Co-Suspension Delivery Technology in patients with moderate-to-very severe COPD.MethodsThese two phase III trials took place over 24 weeks and were randomized, double blind, and placebo controlled; 2,103 and 1,615 patients (40-80 years of age), respectively, were randomized. Patients received GFF MDI, GP MDI 18 μg, FF MDI 9.6 μg, or placebo MDI (all twice daily), or tiotropium 18 μg dry powder inhaler (once daily in PINNACLE-1 only [open-label active comparator]). Efficacy and safety were assessed.ResultsAt week 24, differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE-1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE-2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms).ConclusionsWe conclude that GFF MDI 18/9.6 μg demonstrated superiority over placebo and monocomponent MDIs and was well tolerated, thus providing an additional treatment option for patients with moderate-to-very severe COPD.Trial RegistryClinicalTrials.gov; No.: NCT01854645 and No. NCT01854658; URL: www.clinicaltrials.gov. Long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone. The Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-1) (NCT01854645) and the Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-2) (NCT01854658) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [FF] 18/9.6-μg (GFF) metered dose inhaler (MDI) formulated using the Co-Suspension Delivery Technology in patients with moderate-to-very severe COPD. These two phase III trials took place over 24 weeks and were randomized, double blind, and placebo controlled; 2,103 and 1,615 patients (40-80 years of age), respectively, were randomized. Patients received GFF MDI, GP MDI 18 μg, FF MDI 9.6 μg, or placebo MDI (all twice daily), or tiotropium 18 μg dry powder inhaler (once daily in PINNACLE-1 only [open-label active comparator]). Efficacy and safety were assessed. At week 24, differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE-1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE-2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms). We conclude that GFF MDI 18/9.6 μg demonstrated superiority over placebo and monocomponent MDIs and was well tolerated, thus providing an additional treatment option for patients with moderate-to-very severe COPD.

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Non-small cell lung cancer (NSCLC) is characterized by early metastasis and has the highest mortality rate among all solid tumors, with the majority of patients diagnosed at an advanced stage where curative therapeutic options are lacking. In this study, we identify a targetable mechanism involving TGFβ elevation that orchestrates tumor progression in this disease. Substantial activation of this pathway was detected in human lung cancer tissues with concomitant downregulation of BAMBI, a negative regulator of the TGFβ signaling pathway. Alterations of epithelial-to-mesenchymal transition (EMT) marker expression were observed in lung cancer samples compared with tumor-free tissues. Distinct alterations in the DNA methylation of the gene regions encoding TGFβ pathway components were detected in NSCLC samples compared with tumor-free lung tissues. In particular, epigenetic silencing of BAMBI was identified as a hallmark of NSCLC. Reconstitution of BAMBI expression in NSCLC cells resulted in a marked reduction of TGFβ-induced EMT, migration, and invasion in vitro, along with reduced tumor burden and tumor growth in vivo In conclusion, our results demonstrate how BAMBI downregulation drives the invasiveness of NSCLC, highlighting TGFβ signaling as a candidate therapeutic target in this setting. Cancer Res; 76(13); 3785-801. ©2016 AACR.

Exacerbations of chronic obstructive pulmonary disease (COPD) are defined as sustained worsening of a patient's condition beyond normal day-to-day variations that is acute in onset, and that may also require a change in medication and/or hospitalization. Exacerbations have a significant and prolonged impact on health status and outcomes, and negative effects on pulmonary function. A significant proportion of exacerbations are unreported and therefore left untreated, leading to a poorer prognosis than those treated. COPD exacerbations are heterogeneous, and various phenotypes have been proposed which differ in biologic basis, prognosis, and response to therapy. Identification of biomarkers could enable phenotype-driven approaches for the management and prevention of exacerbations. For example, several biomarkers of inflammation can help to identify exacerbations most likely to respond to oral corticosteroids and antibiotics, and patients with a frequent exacerbator phenotype, for whom preventative treatment is appropriate. Reducing the frequency of exacerbations would have a beneficial impact on patient outcomes and prognosis. Preventative strategies include modification of risk factors, treatment of comorbid conditions, the use of bronchodilator therapy with long-acting β2-agonists or long-acting muscarinic antagonists, and inhaled corticosteroids. A better understanding of the mechanisms underlying COPD exacerbations will help to optimize use of the currently available and new interventions for preventing and treating exacerbations.

Safety concerns regarding long-acting β2-agonists (LABAs) in asthma management were initially identified in a large postmarketing trial in which the risk of death was increased. In 2010, the Food and Drug Administration (FDA) mandated that the four companies marketing LABAs for asthma perform prospective, randomized, controlled trials comparing the safety of combination therapy with a LABA plus an inhaled glucocorticoid with that of an inhaled glucocorticoid alone in adolescents (12 to 17 years of age) and adults. In conjunction with the FDA, the manufacturers harmonized their trial methods to allow an independent joint oversight committee to provide a final combined analysis of the four trials.

The publication of the 2017 report of the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease [2] marks the 20th anniversary of its birth back in 1997. The first Global Initiative for Chronic Obstructive Lung Disease (GOLD) Executive Summary was published in 2001 [3] and since then, GOLD updates the document annually and publishes a major report (revision) every five years. Thus, major reports have been published in 2006 [4], 2011 [5] and 2017 [6]. A brief history of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) on its 20th anniversary <http://ow.ly/rcFE30bZVZ0> Authors thank Rebecca Dekker, current Program Director of GOLD and Global Initiative for Asthma, for her current daily work in support of GOLD activities.

Zusammenfassung Seit Dezember 2019 verbreitet sich das neuartige Coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome – Corona Virus-2) rasch im Sinne einer weltweiten Pandemie. Dies stellt Kliniker und Krankenhäuser vor große Herausforderungen und belastet die Gesundheitssysteme vieler Länder in einem nie dagewesenen Ausmaß. Die Mehrheit der Patienten mit Coronavirus Disease 2019 (COVID-19) zeigt lediglich milde Symptome wie Husten und Fieber. Allerdings benötigen etwa 8 % eine stationäre Behandlung. Der frühzeitigen Klärung, ob eine stationäre und ggfs. intensivmedizinische Behandlung medizinisch sinnvoll und vom Patienten gewollt ist, kommt in der Pandemie eine besondere Bedeutung zu. Die akute hypoxämische respiratorische Insuffizienz mit Dyspnoe und hoher Atemfrequenz (&gt; 30/min) führt i. d. R. zur Aufnahme auf die Intensivstation. Oft finden sich dann bereits bilaterale pulmonale Infiltrate/Konsolidierungen oder auch Lungenembolien in der Bildgebung. Im weiteren Verlauf entwickeln einige dieser Patienten ein akutes Lungenversagen (Acute Respiratory Distress Syndrome; ARDS). Eine Sterblichkeitsreduktion einer verfügbaren medikamentösen Therapie bei schwerer COVID-19-Erkrankung ist bisher lediglich für Dexamethason in randomisiert, kontrollierten Studien nachgewiesen. Das Hauptziel der supportiven Therapie besteht in der Sicherstellung einer ausreichenden Oxygenierung. Die invasive Beatmung und wiederholte Bauchlagerung sind dabei wichtige Elemente in der Behandlung von schwer hypoxämischen COVID-19-Patienten. Die strikte Einhaltung der Basishygiene, einschließlich der Händehygiene, sowie das korrekte Tragen von adäquater persönlicher Schutzausrüstung sind im Umgang mit den Patienten unabdingbar. Medizinisch notwendige Handlungen am Patienten, die zur Aerosolbildung führen könnten, sollten mit äußerster Sorgfalt und Vorbereitung durchgeführt werden.

Little is known about the role of small airway dysfunction (SAD) and its complex relation with asthma control and physical activity (PA).To investigate the interrelations among SAD, risk factors for asthma severity, symptom control, and PA.We assessed SAD by impulse oscillometry and other sophisticated lung function measures including inert gas washout in adults with asthma (mild to moderate, n = 140; severe, n = 128) and 69 healthy controls from the All Age Asthma Cohort. We evaluated SAD prevalence and its interrelation with risk factors for asthma severity (older age, obesity, and smoking), type 2 inflammation (sputum and blood eosinophils, fractional exhaled nitric oxide), systemic inflammation (high-sensitivity C-reactive protein), asthma control (AC), and PA (accelerometer for 1 week). We applied a clinical model based on structural equation modeling that integrated causal pathways among these clinical variables.The prevalence of SAD ranged from 75% to 90% in patients with severe asthma and from 53% to 64% in mild to moderate asthma. Severe SAD was associated with poor AC and low PA. Structural equation modeling indicated that age, obesity, obesity-related systemic inflammation, T2 inflammation, and smoking are independent predictors of SAD. Small airway dysfunction was the main determinant factor of AC, which in turn affected PA. Obesity affected AC directly and through its contribution to SAD and low PA. In addition, PA had bidirectional associations with obesity, SAD, and AC. Structural equation modeling also indicated interrelations among distal airflow limitation, air trapping, and ventilation heterogeneity.Small airway dysfunction is a highly prevalent key feature of asthma that interrelates a spectrum of distal lung function abnormalities with risk factors for asthma severity, asthma control, and physical activity.

Chest computed tomography (CT) is increasingly used for phenotyping and monitoring of patients with COPD. The aim of this work was to evaluate the association of Pi10 as a measure of standardized airway wall thickness on CT with exacerbations, mortality, and response to triple therapy.Patients of GOLD grades 1-4 of the COSYCONET cohort with prospective CT scans were included. Pi10 was automatically computed and analyzed for its relationship to COPD severity, comorbidities, lung function, respiratory therapy, and mortality over a 6-year period, using univariate and multivariate comparisons.We included n = 433 patients (61%male). Pi10 was dependent on both GOLD grades 1-4 (p = 0.009) and GOLD groups A-D (p = 0.008); it was particularly elevated in group D, and ROC analysis yielded a cut-off of 0.26 cm. Higher Pi10 was associated to lower FEV1 % predicted and higher RV/TLC, moreover the annual changes of lung function parameters (p < 0.05), as well as to an airway-dominated phenotype and a history of myocardial infarction (p = 0.001). These associations were confirmed in multivariate analyses. Pi10 was lower in patients receiving triple therapy, in particular in patients of GOLD groups C and D. Pi10 was also a significant predictor for mortality (p = 0.006), even after including multiple other predictors.In summary, Pi10 was found to be predictive for the course of the disease in COPD, in particular mortality. The fact that Pi10 was lower in patients with severe COPD receiving triple therapy might hint toward additional effects of this functional therapy on airway remodeling.ClinicalTrials.gov, Identifier: NCT01245933.

Failure to follow asthma management guidelines may result in poor asthma control for many patients. The Asthma Insights and Reality in Europe (AIRE) survey, a multi-national survey assessing the level of asthma control from the patients perspective in seven Western European countries, previously demonstrated that the Global Initiative for Asthma (GINA) guideline goals were not achieved in Western Europe and that both adults and children with asthma were poorly controlled. Using additional data on asthma management practices from each of the seven countries in the AIRE survey, we compared variations in asthma morbidity and asthma management practices across countries to provide insight into the reasons for poor asthma control. Asthma management practices and asthma control among adults and children with current asthma were suboptimal in each of seven countries surveyed. Among patients with symptoms of severe persistent asthma, over 40% reported their asthma was well or completely controlled. School absence due to asthma was reported by upto 52.7% of children and up to 27.6% of adult reported work absence due to asthma. Lung function testing in the past year was uncommon: ranging from 13.5% of children in the U.K. to 68.8% of adults in Germany. Written asthma management plans were used by less than 50% of adults and less than 61% of children in all seven countries. Most adults (49.5-73.0%) and a large proportion of children (38.4-70.6%) had follow-up visits for their asthma only when problems developed. The ratio of recent inhaled corticosteroid use to recent short-acting beta-agonist use was inappropriate (<1) among patients with symptoms of severe asthma in all countries. This disparity was greatest among adults in Italy and France, where recent inhaled corticosteroid use was reported by less than one in nine patients reporting recent use of short-acting bronchodialators (IS:SAB <0.11). Management practices differ between countries and additional public health interventions and resources may be necessary to reduce patient suffering. Further efforts to fully implement asthma management guidelines are required to improve asthma control in Europe.

Antimicrobial peptides have been identified as key elements in the innate host defense against infection. Recent studies have indicated that the activity of antimicrobial peptides may be decreased in cystic fibrosis, suggesting a major role for these peptides in host defense against infection. One of the most intensively studied classes of antimicrobial peptides are defensins. Defensins comprise a family of cationic peptides that in human subjects can be divided into the alpha- and beta-defensin subfamilies. The alpha-defensins are produced by neutrophils and intestinal Paneth's cells, whereas beta-defensins are mainly produced by epithelial cells. Although studies on beta-defensins have so far focused on their antimicrobial activity, studies on alpha-defensins have suggested a role of these peptides in inflammation, wound repair, and specific immune responses. alpha-Defensins, which accumulate in airway secretions of patients with various chronic inflammatory lung disorders, were shown to be cytotoxic toward airway epithelial cells and to induce chemokine secretion in several cell types. Furthermore, the capacity of alpha-defensins to promote bacterial adherence to epithelial cells in vitro further supports a role for these peptides in the pathogenesis of chronic obstructive pulmonary disease and cystic fibrosis. Increased numbers of neutrophils are also present in the airways of patients with asthma, suggesting that neutrophils are involved in the pathogenesis of this disease. Because defensins are able to induce histamine release by mast cells and increase the airway hyperresponsiveness to histamine, it is tempting to speculate that defensins may also contribute to the inflammatory processes in asthma. Besides these proinflammatory effects, alpha-defensins may also display anti-inflammatory activities, including regulation of complement activation and proteinase inhibitor secretion. Finally, defensins may be involved in wound repair because defensins increase epithelial cell proliferation. Thus recent defensin research has revealed potential links between the innate and acquired immune system.

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High retention of inhaled glucocorticoids in the airways means prolonged anti-inflammatory action and low delivery into the serum. The objective of this study was to investigate the retention in and distribution of inhaled fluticasone propionate (FP) between central and peripheral human lung tissue and serum in vivo. In 17 patients undergoing lung resection surgery, a single 1.0 mg dose of FP was inhaled at varying time-points (range 2.8-21.7 h) preoperatively. Peripheral and central lung tissue was obtained, and blood was drawn simultaneously. FP concentrations in central lung tissue were approximately three to four times higher than peripheral lung tissue concentrations, which in turn, exceeded those found in serum by 10 times. FP was detectable up to 21 and 16 h, respectively, after inhalation, with drug levels falling almost in parallel in peripheral lung tissue and in serum. The results of this study demonstrate that fluticasone propionate is retained in lung tissue for a long time. Serum concentrations after a single inhaled dose are low. Retention of high concentrations of fluticasone propionate in the airways may promote high topical anti-inflammatory activity.

Diagnosis and assessment of treatment effect in chronic obstructive pulmonary disease (COPD) have relied primarily on the examination of a complex set of symptoms and the use of spirometry. However, these methods require long periods of assessment to determine whether patients show clinically relevant improvements after intervention. We therefore wanted to determine how existing clinical and laboratory measures change with COPD severity and identify disease markers that can serve as better endpoints for diagnosis and assessment of COPD progression and treatment effect. Using standard COPD keywords and terms, we searched PubMed, ISI Web of Science, and Cochrane Review databases for retrospective and prospective clinical studies published since 1966. We identified 652 studies (n=146,255) from 1978 to September 2003 based on the availability of spirometric and demographic data, investigation of possible markers, absence of acute exacerbations and co-morbidities, and the withdrawal of standard COPD medication. Central tendencies and dispersions of subject baseline measures were collected according to study sample size, smoking status, and mild, moderate and severe COPD stages. A fixed effect meta-analysis was then conducted on each measure at various disease stages. Arterial oxygen tension, sputum neutrophils and IL-8, and serum TNF-α and C-Reactive Protein showed a trend toward separation between COPD stages. Other measures such as pack-years and St George's Respiratory Questionnaire only distinguished between disease and disease-free states. We observed little separation between disease stages for many measures used in COPD diagnosis and clinical trials. This demonstrates the poor sensitivity of such endpoints to define a patient's clinical status and to quantify treatment effect. Therefore, we recommend that longitudinal studies and disease modelling be the primary methods for assessing whether potential markers of disease progression can be used for COPD diagnosis and clinical trials.

Persistent airflow limitation may develop in patients with asthma, particularly in adults with nonatopic (intrinsic) disease. Although the underlying mechanisms are still unknown, respiratory infections might be involved.We investigated the annual loss of lung function in relation to seropositivity to Chlamydia pneumoniae in different subgroups of patients with severe asthma according to age at onset of asthma and atopic status.One hundred one nonsmoking outpatients with a pulmonologist's diagnosis of severe asthma (32 men and 69 women; mean age, 46.0 years; range, 18-75 years) were included in a cross-sectional study. C pneumoniae-specific serum IgG and IgA were measured by means of ELISA. The estimated decline in lung function was calculated from the relationship between postbronchodilator FEV(1)/vital capacity (percent predicted) and the duration of asthma and expressed as the slope of the regression line.Patients with adult-onset nonatopic asthma and positive IgG antibodies to C pneumoniae had a significantly steeper slope of the regression line compared with the other subgroups of asthmatic patients (P =.001), being indicative of a 4-fold greater estimated decline in postbronchodilator FEV(1)/vital capacity (2.3% vs 0.5% predicted per year of asthma duration).These results suggest that C pneumoniae infection might promote the development of persistent airflow limitation in patients with nonatopic adult-onset asthma. It remains to be established whether viable pathogens that are accessible for therapeutic intervention are still present in the lower airways.

Alveolar nitric oxide (NO) is a measure of peripheral airway inflammation in asthma, potentially associated with disease severity. The relationship between alveolar NO and physiological tests of peripheral airway (dys)function has not been investigated. The present authors hypothesised that peripheral airway inflammation and dysfunction are inter-related and associated with asthma severity. Alveolar NO was compared between 17 patients with mild-to-moderate asthma and 14 patients with severe asthma and related to total lung capacity (TLC), residual volume (RV)/TLC, thoracic gas volume (FRC), slope of the single breath nitrogen washout curve (dN2), closing capacity (CC)/TLC and fall in forced vital capacity at the provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second. In patients with severe asthma, strong correlations were found between alveolar NO and RV/TLC % pred, FRC % pred, dN2, and CC/TLC. Patients with oral steroid-dependent asthma had higher alveolar NO levels (2.7 ppb) compared with the other patients with severe (0.6 ppb) and mild-to-moderate asthma (0.3 ppb). The present authors conclude that alveolar nitric oxide is closely related to parameters of peripheral airway dysfunction in patients with severe asthma, and that oral steroid-dependent asthmatics have more peripheral airway disease than nonsteroid-dependent asthmatics. This suggests that patients on chronic oral steroid treatment have more extensive disease and require additional anti-inflammatory treatment to better target the peripheral airways.