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Dysfunctional breathing phenotype in adults with asthma - incidence and risk factors
Ioana Agache, Cristina Ciobanu, Gabriela Paul, Liliana Rogozea
Clinical and Translational Allergy , 2012, DOI: 10.1186/2045-7022-2-18
Abstract: Adult patients aged 17–65 with diagnosed asthma were screened for DB using the Nijmegen questionnaire (positive predictive score >23) and confirmed by progressive exercise testing. The following were evaluated as independent risk factors for DB in the multiple regression analysis: female sex; atopy, obesity, active smoker, moderate/severe rhinitis, psychopathology, GERD, arterial hypertension; severe asthma, asthma duration > 5 years, lack of asthma control, fixed airway obstruction, fast lung function decline, frequent exacerbator and brittle asthma phenotypes; lack of ICS, use of LABA or LTRA.91 adults with asthma, mean age 35.04 ±1.19 years, 47(51.65%) females were evaluated. 27 (29.67%) subjects had a positive screening score on Nijmegen questionnaire and 16(17.58%) were confirmed by progressive exercise testing as having DB. Independent risk factors for DB were psychopathology (p = 0.000002), frequent exacerbator asthma phenotype (p = 0.01) and uncontrolled asthma (p < 0.000001).Dysfunctional breathing is not infrequent in asthma patients and should be evaluated in asthma patients presenting with psychopathology, frequent severe asthma exacerbations or uncontrolled asthma. Asthma medication (ICS, LABA or LTRA) had no significant relation with dysfunctional breathing.Dysfunctional breathing (DB) is defined as chronic or recurrent changes in breathing pattern that cannot be attributed to a specific medical diagnosis, causing respiratory and non-respiratory complaints such as anxiety, light headedness and fatigue. Symptoms of DB include dyspnea with normal lung function, chest tightness, chest pain, deep sighing, exercise-induced breathlessness, frequent yawning and hyperventilation [1-6]. There is no gold standard for the diagnosis of DB beyond the clinical description. The Nijmegen Questionnaire can be used to discriminate dysfunctional breathers from normal individuals in adults [7]. For moderate to severe asthma a positive Nijmegen score might overestimate the
Application of the Asthma Phenotype Algorithm from the Severe Asthma Research Program to an Urban Population  [PDF]
Paru Patrawalla, Angeliki Kazeros, Linda Rogers, Yongzhao Shao, Mengling Liu, Maria-Elena Fernandez-Beros, Shulian Shang, Joan Reibman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044540
Abstract: Rationale Identification and characterization of asthma phenotypes are challenging due to disease complexity and heterogeneity. The Severe Asthma Research Program (SARP) used unsupervised cluster analysis to define 5 phenotypically distinct asthma clusters that they replicated using 3 variables in a simplified algorithm. We evaluated whether this simplified SARP algorithm could be used in a separate and diverse urban asthma population to recreate these 5 phenotypic clusters. Methods The SARP simplified algorithm was applied to adults with asthma recruited to the New York University/Bellevue Asthma Registry (NYUBAR) to classify patients into five groups. The clinical phenotypes were summarized and compared. Results Asthma subjects in NYUBAR (n = 471) were predominantly women (70%) and Hispanic (57%), which were demographically different from the SARP population. The clinical phenotypes of the five groups generated by the simplified SARP algorithm were distinct across groups and distributed similarly to those described for the SARP population. Groups 1 and 2 (6 and 63%, respectively) had predominantly childhood onset atopic asthma. Groups 4 and 5 (20%) were older, with the longest duration of asthma, increased symptoms and exacerbations. Group 4 subjects were the most atopic and had the highest peripheral eosinophils. Group 3 (10%) had the least atopy, but included older obese women with adult-onset asthma, and increased exacerbations. Conclusions Application of the simplified SARP algorithm to the NYUBAR yielded groups that were phenotypically distinct and useful to characterize disease heterogeneity. Differences across NYUBAR groups support phenotypic variation and support the use of the simplified SARP algorithm for classification of asthma phenotypes in future prospective studies to investigate treatment and outcome differences between these distinct groups. Trial Registration Clinicaltrials.gov NCT00212537
Asma agudo severo en ni os: Fenotipo diferente? Severe asthma in children: A different phenotype?  [cached]
Jaime Lozano C,Leticia Yá?ez P,Michelangelo Lapadula A,Carlos Fernández C
Revista Chilena de Enfermedades Respiratorias , 2012,
Abstract: La magnitud de la respuesta al tratamiento de una exacerbación de asma es variable entre los pacientes y una proporción significativa de ellos debe hospitalizarse. Objetivos: Definir el perfil de los ni os que se hospitalizaron por asma grave y los posibles indicadores y determinantes de la respuesta desfavorable al tratamiento. Método: Estudio prospectivo en ni os de 4 a os o más, con búsqueda etiológica de la exacerbación y estudio de perfil inflamatorio en esputo. Resultados: 60 ni os entre 4 y 15 a os. El 50% tenía diagnóstico previo de asma sin uso regular de corticoesteroides inhalados en dos tercios. Hospitalizaciones previas por asma en el 40%. La etiología de la exacerbación fue identificada en el 52% siendo los agentes más frecuentes Rhinovirus, Metapneumovius, VRS y Mycoplasma pneumoniae. El perfil inflamatorio fue determinado en 33 ni os: eosinofílico en 36% y eosinoflico/neutroflico en 64%. Comentario: El asma severa con exacerbaciones graves sería un fenotipo cuyos aspectos destacados en esta cohorte serían: ni os con hospitalizaciones previas, falta de tratamiento profiláctico, infección viral como desencadenante frecuente, patrón inflamatorio combinado del esputo y rinitis atópica. Background: The magnitude of response to treatment of asthma exacerbations is variable and a significant proportion of them need hospitalization. Objectives: to define the profile of children that were hospitalized for severe asthma and the possible indicators and determinants of their poor responsiveness. Methods: a prospective study in 60 children 4 years or more of age with a search of the ethiology of the exacerbation and a study of the inflammatory profile in sputum. Results: 60 children between 4 and 15 years. 50% had a previous diagnosis of asthma without regular use of inhaled corticosteroids in two thirds. 40% had previous admissions for asthma. Etiology of the exacerbation was identified in 52% with Rhinovirus, human Metapneumovirus, RSV and Mycoplasma pneumoniae as the most frequent agents. Inflammatory profile was determined in 33 children: eosinophilic in 36%, eosinophilic/ neutrophilic in 64%. Conclusions: Severe asthma with serious exacerbations may be a phenotype whose outstanding aspects in this cohort were: previous hospitalizations, lack of prophylactic treatment, viral infections as frequent trigger, and combined inflammatory cell profile in sputum.
Statistical Cluster Analysis of the British Thoracic Society Severe Refractory Asthma Registry: Clinical Outcomes and Phenotype Stability  [PDF]
Chris Newby, Liam G. Heaney, Andrew Menzies-Gow, Rob M. Niven, Adel Mansur, Christine Bucknall, Rekha Chaudhuri, John Thompson, Paul Burton, Chris Brightling, on behalf of the British Thoracic Society Severe Refractory Asthma Network
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0102987
Abstract: Background Severe refractory asthma is a heterogeneous disease. We sought to determine statistical clusters from the British Thoracic Society Severe refractory Asthma Registry and to examine cluster-specific outcomes and stability. Methods Factor analysis and statistical cluster modelling was undertaken to determine the number of clusters and their membership (N = 349). Cluster-specific outcomes were assessed after a median follow-up of 3 years. A classifier was programmed to determine cluster stability and was validated in an independent cohort of new patients recruited to the registry (n = 245). Findings Five clusters were identified. Cluster 1 (34%) were atopic with early onset disease, cluster 2 (21%) were obese with late onset disease, cluster 3 (15%) had the least severe disease, cluster 4 (15%) were the eosinophilic with late onset disease and cluster 5 (15%) had significant fixed airflow obstruction. At follow-up, the proportion of subjects treated with oral corticosteroids increased in all groups with an increase in body mass index. Exacerbation frequency decreased significantly in clusters 1, 2 and 4 and was associated with a significant fall in the peripheral blood eosinophil count in clusters 2 and 4. Stability of cluster membership at follow-up was 52% for the whole group with stability being best in cluster 2 (71%) and worst in cluster 4 (25%). In an independent validation cohort, the classifier identified the same 5 clusters with similar patient distribution and characteristics. Interpretation Statistical cluster analysis can identify distinct phenotypes with specific outcomes. Cluster membership can be determined using a classifier, but when treatment is optimised, cluster stability is poor.
The Asthma Phenotype in the Obese: Distinct or Otherwise?  [PDF]
Sherry Farzan
Journal of Allergy , 2013, DOI: 10.1155/2013/602908
Abstract: Asthma is a heterogenous disorder that can be classified into several different phenotypes. Recent cluster analyses have identified an “obese-asthma” phenotype which is characterized by late onset, female predominance and lack of atopy. In addition, obesity among early-onset asthmatics clearly exists and heightens the clinical presentation. Observational studies have demonstrated that asthma among the obese has a clinical presentation that is more severe, harder to control, and is not as responsive to standard controller therapies. While weight loss studies have demonstrated improvement in asthma outcomes, further studies need to be performed. The current knowledge of the existence of two obesity-asthma phenotypes (early- versus late-onset asthma) should encourage investigators to study these entities separately since just as they have distinct presentations, their course, response to therapies, and weight loss strategies may be different as well. 1. Introduction Although the clinical definition of asthma, a chronic inflammatory disorder of the airways characterized by bronchial hyperresponsiveness and airway obstruction resulting in respiratory symptoms, is uniform in the over 300 million individuals affected worldwide [1], clinicians diagnosing, treating and managing asthma can unequivocally agree that it is a heterogeneous disease. The clinical spectrum of disease, inflammatory milieu, demographic characteristics, and comorbidities define the asthma phenotype. Phenotype, defined as the set of observable characteristics of an organism that are produced by the interactions of the genotype and the environment, in asthma can be defined based upon a number of factors, including age of onset, atopy, inflammatory infiltrates, severity of disease, response to standard medications as well as a number of other factors. Delving deeper into the pathophysiology of the disease and the resulting endotype of asthma may help to tailor clinician’s management of these diverse presentations of a single disease. The clinician’s experience of such a diversity of asthma presentations has been supported by a plethora of observational and clinical studies as well as a number of recent cluster analyses which use statistical methods to categorize asthmatics based upon clinical and demographic factors. One phenotype which has been suggested in clinical studies and consistently identified in cluster analyses is that of an “asthma-obesity” phenotype. With the rising epidemics of both asthma and obesity in the United States, the “asthma-obesity” phenotype is attracting more
Role of Obesity in Asthma Control, the Obesity-Asthma Phenotype  [PDF]
Shannon Novosad,Supriya Khan,Bruce Wolfe,Akram Khan
Journal of Allergy , 2013, DOI: 10.1155/2013/538642
Abstract: Asthma is a disease with distinct phenotypes that have implications for both prognosis and therapy. Epidemiologic studies have demonstrated an association between asthma and obesity. Further studies have shown that obese asthmatics have poor asthma control and more severe asthma. This obese-asthma group may represent a unique phenotype. The mechanisms behind poor asthma control in obese subjects remain unclear, but recent research has focused on adipokines and their effects on the airways as well as the role of oxidative stress. Both surgical and nonsurgical weight loss therapy have shown promising results with improvements in asthma control and decreased asthma severity. Comorbid conditions such as gastroesophageal reflux disease and obstructive sleep apnea may also have a role in poor asthma control in obese asthmatics. Further research is needed to define the mechanisms behind this phenotype which will guide the development of targeted therapies. 1. Introduction to the Obese-Asthma Phenotype Obesity and asthma are major public health problems affecting large numbers of individuals across the globe. Obesity is often classified using body mass index (BMI) (Table 1) [1]. Worldwide obesity has more than doubled since 1980. In 2008, more than 1.4 billion adults, ≥20 years, were overweight. Of these, over 200 million men and nearly 300 million women were obese. It is estimated that at least 2.8 million adults die each year as a result of being overweight or obese [2]. Table 1: WHO body mass index (BMI) Classification [ 1]. The World Health Organization estimates that 235 million people currently suffer from asthma and that asthma is under diagnosed and undertreated [3]. Asthma prevalence (the percentage of people who have ever been diagnosed with asthma and still have asthma) increased from 7.3% in 2001 to 8.4% in 2010 in the United States [4]. In 2010, an estimated 25.7 million people had asthma: 18.7 million adults aged 18 and over, and 7.0 million children aged 0–17 years [4]. Both cross-sectional epidemiologic investigations and prospective studies have shown an association between asthma and obesity with a relative risk (RR) of up to 3.0 [5–8]. A meta-analysis of seven prospective studies showed an increased odds ratio (OR) for incident asthma of 1.92 (1.43–2.59) in those with obesity versus normal weight and concluded that the odds of incident asthma increased by 50% in overweight/obese individuals [9]. There was a dose-response relationship between body weight and asthma with increasing odds of incident asthma as BMI increased ( for trend) [9].
Severe asthma and the omalizumab option
Christopher WT Miller, Narayanaswamy Krishnaswamy, Chambless Johnston, Guha Krishnaswamy
Clinical and Molecular Allergy , 2008, DOI: 10.1186/1476-7961-6-4
Abstract: Asthma is a chronic inflammatory airway disease characterized by infiltration of the mucosa by inflammatory cells, mucus hypersecretion, subbasement membrane fibrosis, smooth muscle hypertrophy, epithelial loss and alterations of angiogenesis [1]. The result of these changes is airway obstruction, a cumulative effect of airway inflammation and remodeling changes. These various definitions are summarized in Table 1. Inflammatory processes that occur in asthma are summarized in Table 2. Several inflammatory events occur in asthma, resulting in the observed pathophysiological (Figure 1) and clinical effects [1-3]. Th2-type T cells secreting a distinctive set of cytokines [such as interleukin (IL)-4, IL-5 and IL-13] play a pivotal role in asthma. We and others have showed that IL-5 transcripts are detectable in the lungs of patients with asthma, dominantly derived from the T cell fraction [4,5]. IL-5 is pivotal to eosinophil activation and survival. The basic driving process in allergic asthma is the class switching to and secretion of IgE by B lymphocytes, in response to cytokines such as IL-4. This defines the atopic phenotype. IgE to environmental allergens (referred to as specific antibody) binds to the respective allergen with high affinity. The allergen interacts with IgE on the surface of human mast cells, and mediates signaling via the high affinity IgE receptor (FcεR1) (Figure 1). FcεR1 aggregation is followed by mast cell activation and degranulation. Mast cells release a plethora of mediators (Figures 1 and 2 and Table 1) which can, in turn, regulate eosinophil activation [6,7], Th2 skewing and B cell class switching to IgE [8,9]. Mast cells can also be activated by IgE-independent mechanisms such as bacterial infection [10], toll-like receptors, IL-1 [11] and by contact with either T cells [12] or fibroblasts [13]. IgE-mediated inflammatory responses may be responsible for a variety of atopic disorders, including rhinitis, asthma, eczema, food allergy, otiti
Emerging therapies for severe asthma
Neil C Thomson, Rekha Chaudhuri, Mark Spears
BMC Medicine , 2011, DOI: 10.1186/1741-7015-9-102
Abstract: Asthma is a chronic inflammatory disease of the airways that affects over 300 million individuals worldwide [1]. The majority of adults with asthma have mild or moderate disease that can be controlled by inhaled corticosteroids either alone or in combination with inhaled long-acting ?2 agonist bronchodilators [1-3]. Questionnaire surveys however indicate that a considerable proportion of these patients [4], as well as most with severe asthma [5], or who are cigarette smokers [6,7] have poorly controlled asthma. Systematic evaluation can help identify patients with severe asthma from those with difficult-to-treat asthma due to poor adherence, untreated co-morbidities, dysfunctional breathing or psychological problems [8,9]. For patients with severe asthma, which accounts for 5% to 10% of cases [10], there is a need for improved therapies [10-12]. This mini-review focuses on biological agents, new inhaled long-acting bronchodilators and corticosteroids, arachidonic acid pathway blockers, bronchial thermoplasty plus a range of other anti-inflammatory agents that have been recently licensed or are at an advanced stage of development for patients with severe asthma (Figure 1). In addition, we briefly discuss the idea that the development of novel therapies for asthma is likely increasingly to involve the assessment of genotypic and/or phenotypic factors.The first and as yet only biological agent licensed for the treatment of asthma is omalizumab, a humanized monoclonal antibody that binds circulating IgE antibody, preventing it from binding to its specific high-affinity receptor on mast cells and basophils [13]. In patients with allergic asthma, omalizumab treatment improves symptoms and reduces exacerbations [14,15]. Clinical trials are also underway to assess the efficacy of omalizumab in non-allergic asthma and in combination with specific allergen immunotherapy, with the aim of reducing systemic allergic reactions [16]. The adverse effect profile of omalizumab is gen
Clinical review: Severe asthma
Spyros Papiris, Anastasia Kotanidou, Katerina Malagari, Charis Roussos
Critical Care , 2002, DOI: 10.1186/cc1451
Abstract: Treatment for acute, severe asthma includes the administration of oxygen, β2-agonists (by continuous or repetitive nebulisation), and systemic corticosteroids. Subcutaneous administration of epinephrine or terbutaline should be considered in patients not responding adequately to continuous nebulisation, in those unable to cooperate, and in intubated patients not responding to inhaled therapy. The exact time to intubate a patient in status asthmaticus is based mainly on clinical judgment, but intubation should not be delayed once it is deemed necessary. Mechanical ventilation in status asthmaticus supports gas-exchange and unloads ventilatory muscles until aggressive medical treatment improves the functional status of the patient. Patients intubated and mechanically ventilated should be appropriately sedated, but paralytic agents should be avoided. Permissive hypercapnia, increase in expiratory time, and promotion of patient-ventilator synchronism are the mainstay in mechanical ventilation of status asthmaticus. Close monitoring of the patient's condition is necessary to obviate complications and to identify the appropriate time for weaning. Finally, after successful treatment and prior to discharge, a careful strategy for prevention of subsequent asthma attacks is imperative.Bronchial asthma has a wide clinical spectrum ranging from a mild, intermittent disease to one that is severe, persistent, and difficult to treat, which in some instances can also be fatal [1,2,3,4]. Asthma deaths, although uncommon (one in 2000 asthmatics), have increased over the last decades [2], with more than 5000 deaths reported annually in the USA and 100,000 deaths estimated yearly throughout the world [1,2]. Patients at greater risk for fatal asthma attacks are mainly those with severe, unstable disease, although death can occur to anyone if the asthma attack is intense enough [2,3,4]. Most deaths from asthma are preventable, however, particularly those among young persons. Morbidity in
The Professional Medical Journal , 2007,
Abstract: Objective: To compare the improvement in peak expiratory flow rate (PEFR) of patients presentingto the emergency department with acute severe asthma by using the following two regimens of broncho-dilator therapy.a) Salbutamol nebulization. b) Salbutamol plus Ipratropium bromide nebulization. c) To compare the hospital admissionrates in the above mentioned two treatment groups. Design: A comparative study. Place and Duration of Study:Military Hospital Rawalpindi, Feb 2002 to Dec 2002. Material and Methods: Sixty adult asthmatic patients with peakexpiratory flow rate (PEFR) less than 200 liters per minute were randomly assigned to nebulization treatment withsalbutamol (5.0 mg initial dose followed by 2 more doses at 30 and 60 minutes) or the same salbutamol regimen plusipratropium bromide (0.5 mg). The primary end point was change in PEFR. The PEFR was measured at 30 minutes,60 minutes and 90 minutes after the onset of study protocol. The proportion of admission in the two groups wasexamined as secondary end point. Results: The increase in PEFR over time was significantly greater in combinedipratropium plus salbutamol group (p = 0.01) also the proportion of admitted patients was less in combined salbutamolplus ipratropium bromide group 4/30 vs 11/30, p = 0.036. Conclusion: The data suggested that combined iratropiumbromide plus salbutamol nebulization was superior to salbutamol nebulization alone and it should be used in the initialmanagement of patients who present with acute severe asthma.
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