Luis Pérez de Llano

Effects of Omalizumab in Non-Atopic Asthma: Results from a Spanish Multicenter Registry

Aim. To evaluate the effectiveness of omalizumab in non-atopic asthma. Methods. Using data from a multicenter registry of severe asthma, we evaluated and compared the clinical outcome of 29 omalizumab-treated severe non-atopic asthmatics with 266 omalizumab-treated severe allergic asthmatics. Effectiveness was assessed by considering severe exacerbations, pulmonary function, the Global Evaluation of Treatment Effectiveness (GETE) scale, and Asthma Control Test (ACT). Results. Omalizumab demonstrated significant improvement in the clinical status of non-atopic asthmatics as measured by GETE, which rose from 1.6 ± 1.1 to 2.8 ± 0.8 at 4 months (p = .0215) to 2.9 ± 0.9 at 1 year (p = .0093) and to 3.4 ± 0.6 at 2 years (p = .0078), and by the ACT, which increased from 13.0 ± 5.5 to 17.5 ± 5.4 at 4 months (p = .0236) to 17.9 ± 4.8 at 1 year (p = .0136) and to 20.6 ± 3.9 at 2 years (p = .0024). Forced expiratory volume in 1 second (FEV1) improved from 61.0 ± 19.4% to 65.1 ± 17.2 at 4 months to 64.1 ± 24.7 at 1 year and to 67.3 ± 23.0 at 2 years, but without significant differences between initial and follow-up measurements (p = .52, .91, and .45, respectively) and exacerbations decreased from 3.1 ± 3.5 to 1.9 ± 2.8 at 1 year (p = .1709) to 1.8 ± 4.4 at 2 years (p = .2344). The results were not significantly different from those obtained in atopic asthmatics. Conclusion. Anti-IgE therapy can be effective in non-atopic severe asthma.

Omalizumab Therapy in Severe Asthma: Experience from the Spanish Registry—Some New Approaches

Objective. The efficacy of omalizumab in severe asthma has been widely demonstrated. The main objective of this study was to evaluate the efficacy and tolerability of omalizumab in a real-life setting in Spain, particularly in those patients with immunoglobulin E (IgE) levels out of range. Methods. Totally 266 uncontrolled severe asthma patients receiving high-dose inhaled corticosteroids (ICSs) plus long-acting β2-agonist (LABA) were recruited. Main efficacy outcomes were asthma exacerbation rate (AER), asthma control test (ACT), and global evaluation of treatment effectiveness (GETE). Results. AER was reduced from 3.6 (3.6) in previous year to 0.67 (1.2) at 4 months (p < .05) and to 1.04 (1.8) at 2 years (p < .05). ACT increased significantly from 14.3 (4.7) at baseline to 18.4 (4.4) at 4 months (p < .05) and to 20.3 (4.0) (p < .05) at 2 years. After 4 months, 74.6% of patients had reached a good or excellent rate on the GETE scale (p < .05). This rate continued increasing up to 81.6% at 2 years. These efficacy results were similar for patients with “off-label” IgE > 700 IU/ml. At follow-up, maintenance treatment with oral steroids was discontinued in a considerable number of patients: from 89 to 19 (p < .05). Omalizumab was discontinued because of lack of efficacy only in 28/266 (10.5%) patients. Overall, 30 patients (11.4%) reported adverse events. Severe adverse events were not observed. Conclusion. This real-life study confirms that omalizumab is very efficacious and very well tolerated in patients with uncontrolled severe asthma. Results did not vary in the subgroup of patients with IgE levels >700 IU/ml.

Distribución de fenotipos clínicos en pacientes con enfermedad pulmonar obstructiva crónica por humo de biomasa y por tabaco

INTRODUCTION Exposure to biomass smoke is a risk factor for chronic obstructive pulmonary disease (COPD). It is unknown whether COPD caused by biomass smoke has different characteristics to COPD caused by tobacco smoke. OBJECTIVE To determine clinical differences between these two types of the disease. METHODS Retrospective observational study of 499 patients with a diagnosis of COPD due to biomass or tobacco smoke. The clinical variables of both groups were compared. RESULTS There were 122 subjects (24.4%) in the biomass smoke group and 377 (75.5%) in the tobacco smoke group. In the tobacco group, the percentage of males was higher (91.2% vs 41.8%, P<.0001) and the age was lower (70.6 vs 76.2 years, P<.0001). Body mass index and FEV1% values were higher in the biomass group (29.4±5.7 vs 28.0±5.1, P=.01, and 55.6±15.6 vs 47.1±17.1, P<.0001, respectively). The mixed COPD-asthma phenotype was more common in the biomass group (21.3% vs 5%, P<.0001), although this difference disappeared when corrected for gender. The emphysema phenotype was more common in the tobacco group (45.9% vs 31.9%, P=.009). The prevalence of the chronic bronchitis and exacerbator phenotypes, the comorbidity burden and the rate of hospital admissions were the same in both groups. CONCLUSION Differences were observed between COPD caused by biomass and COPD caused by tobacco smoke, although these may be attributed in part to uneven gender distribution between the groups.

Obesity-Hypoventilation Syndrome: Increased Risk of Death over Sleep Apnea Syndrome

Aim To study whether mortality and cardiovascular morbidity differ in non-invasive ventilation (NIV)-treated patients with severe obesity-hypoventilation syndrome (OHS) as compared with CPAP-treated patients with obstructive sleep apnea syndrome (OSAS), and to identify independent predictors of mortality in OHS. Material and methods Two retrospective cohorts of OHS and OSAS were matched 1:2 according to sex, age (±10 year) and length of time since initiation of CPAP/NIV therapy (±6 months). Results Three hundred and thirty subjects (110 patients with OHS and 220 patients with OSAS) were studied. Mean follow-up time was 7±4 years. The five year mortality rates were 15.5% in OHS cohort and 4.5% in OSAS cohort (p< 0.05). Patients with OHS had a 2-fold increase (OR 2; 95% CI: 1.11–3.60) in the risk of mortality and 1.86 fold (OR 1.86; 95% CI: 1.14–3.04) increased risk of having a cardiovascular event. Diabetes, baseline diurnal SaO2 < 83%, EPAP < 7 cmH2O after titration and adherence to NIV < 4 hours independently predicted mortality in OHS. Conclusion Mortality of severe OHS is high and substantially worse than that of OSAS. Severe OHS should be considered a systemic disease that encompasses respiratory, metabolic and cardiovascular components that require a multimodal therapeutic approach.

What pulmonologists think about the asthma-COPD overlap syndrome.

Background Some patients with COPD may share characteristics of asthma; this is the so-called asthma–COPD overlap syndrome (ACOS). There are no universally accepted criteria for ACOS, and most treatments for asthma and COPD have not been adequately tested in this population. Materials and methods We performed a survey among pulmonology specialists in asthma and COPD aimed at collecting their opinions about ACOS and their attitudes in regard to some case scenarios of ACOS patients. The participants answered a structured questionnaire and attended a face-to-face meeting with the Metaplan methodology to discuss different aspects of ACOS. Results A total of 26 pulmonologists with a mean age of 49.7 years participated in the survey (13 specialists in asthma and 13 in COPD). Among these, 84.6% recognized the existence of ACOS and stated that a mean of 12.6% of their patients might have this syndrome. In addition, 80.8% agreed that the diagnostic criteria for ACOS are not yet well defined. The most frequently mentioned characteristics of ACOS were a history of asthma (88.5%), significant smoking exposure (73.1%), and postbronchodilator forced expiratory volume in 1 second/forced vital capacity <0.7 (69.2%). The most accepted diagnostic criteria were eosinophilia in sputum (80.8%), a very positive bronchodilator test (69.2%), and a history of asthma before 40 years of age (65.4%). Up to 96.2% agreed that first-line treatment for ACOS was the combination of a long-acting β2-agonist and inhaled steroid, with a long-acting antimuscarinic agent (triple therapy) for severe ACOS. Conclusion Most Spanish specialists in asthma and COPD agree that ACOS exists, but the diagnostic criteria are not yet well defined. A previous history of asthma, smoking, and not fully reversible airflow limitation are considered the main characteristics of ACOS, with the most accepted first-line treatment being long-acting β2-agonist/inhaled corticosteroids.

Algorithm for identification of asthma–COPD overlap: consensus between the Spanish COPD and asthma guidelines

It was as early as 1959 that the report of the CIBA Symposium described the possible coexistence of different obstructive airway diseases, such as asthma, chronic bronchitis and/or emphysema, in the same individual. However, because there were no specific therapies for all these different expressions of lung disease, these overlaps were largely ignored by guidelines. In 1995, the American Thoracic Society chronic obstructive pulmonary disease (COPD) statement included a Venn diagram with the different possible overlaps of clinical presentation of obstructive lung diseases [1], but no specific recommendations of treatment were provided for them. It was not until 2007 that the Canadian COPD guidelines specified that: “if the asthma component (in COPD) is prominent, earlier introduction of inhaled corticosteroids (ICS) may be justified” [2]. Later, in 2010, the Japanese guidelines for COPD dedicated a chapter to “Treatment of COPD complicated by asthma” [3]. To the best of our knowledge, the Spanish guidelines for COPD (GesEPOC) in 2012 were the first to propose specific criteria for the identification of the so-called asthma–COPD overlap (ACO) [4, 5]. Because there was no internationally accepted definition of ACO, a group of experts proposed diagnostic criteria for ACO in COPD [6] and these were adopted in the document. The major criteria were as follows: a very positive bronchodilator response (>400 mL and >15% increase in forced expiratory volume in 1 s (FEV1)), sputum eosinophilia or a previous diagnosis of asthma. Minor criteria were an increased total serum IgE, previous history of atopy or a positive bronchodilator test (>200 mL and >12% in FEV1) on at least two occasions [6]. To be diagnosed with ACO, a patient must fulfil two major or one major and two minor criteria. Other national guidelines for COPD, such as the Finnish [7] and the Czech guidelines [8], followed this approach and proposed similar criteria for ACO. An algorithm to identify patients with ACO rather than asthma or COPD alone http://ow.ly/Viyy308Ehdk

Consenso sobre el solapamiento de asma y EPOC (ACO) entre la Guía española de la EPOC (GesEPOC) y la Guía Española para el Manejo del Asma (GEMA)

Following a proposal by the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), sponsor of the Spanish COPD Guidelines (GesEPOC) and the Spanish Guidelines on the Management of Asthma (GEMA), authors of both papers have unified the criteria for the diagnosis of asthma-COPD overlap syndrome (ACOS). This consensus defines ACOS as the presence in a given patient of three elements: significant smoking exposure, chronic airflow limitation and asthma. Diagnosis is confirmed when a patient (35years of age or older), smoker or ex-smoker of more than 10 pack-years, presents airflow limitation (post-bronchodilator FEV1/FVC<0.7) that persists after treatment with bronchodilators and inhaled corticosteroids (even after systemic corticosteroids in selected cases), and an objective current diagnosis of asthma (according to GEMA criteria). In cases in which the diagnosis of asthma cannot be demonstrated, marked positive results on a bronchodilator test (FEV1≥15% and ≥400mL) or elevated blood eosinophil count (≥300eosinophils/μL) will also be diagnostic of ACOS. The opinion of another 33 experts who had not participated in the consensus was sought using a modified Delphi survey. Up to 80% of respondents gave a very positive opinion of the consensus, and declared that it was better than other previous proposals. The GesEPOC-GEMA consensus on ACOS provides a unique perspective of the diagnostic problem, using a simple proposal and a pragmatic diagnostic algorithm that can be applied at any healthcare level.

Th-2 signature in chronic airway diseases: towards the extinction of asthma−COPD overlap syndrome?

We aimed to describe the differences and similarities between patients with chronic obstructive airway disease classified on the basis of classical diagnostic labels (asthma, chronic obstructive pulmonary disease (COPD), or asthma–COPD overlap (ACOS)) or according to the underlying inflammatory pattern (Th-2 signature, either Th-2-high or Th-2-low). We performed a cross-sectional study of patients aged ≥40 years and with a post-bronchodilator forced expiratory volume in 1 s to forced vital capacity ratio ≤0.7 with a previous diagnosis of asthma (non-smoking asthmatics (NSA)), COPD or ACOS, the latter including both smoking asthmatics (SA) and patients with eosinophilic COPD (COPD-e). Clinical, functional and inflammatory parameters (blood eosinophil count, IgE and exhaled nitric oxide fraction (FeNO)) were compared between groups. Th-2 signature was defined by a blood eosinophil count ≥300 cells·μL−1 and/or a sputum eosinophil count ≥3%. Overall, 292 patients were included in the study: 89 with COPD, 94 NSA and 109 with ACOS (44 SA and 65 with COPD-e). No differences in symptoms or exacerbation rate were found between the three groups. With regards the underlying inflammatory pattern, 94 patients (32.2%) were characterised as Th-2-high and 198 (67.8%) as Th-2-low. The Th-2 signature was found in 49% of NSA, 3.3% of patients with COPD, 30% of SA and 49.3% of patients with COPD-e. This classification yielded significant differences in demographic, functional and inflammatory characteristics. We conclude that a classification based upon the inflammatory profile, irrespective of the taxonomy, provides a more clear distinction of patients with chronic obstructive airway disease. Identifying a Th-2 signature in patients with chronic airflow limitation effectively differentiates treatable traits http://ow.ly/kq1E309MMkt

Relación entre presencia de comorbilidad y control del asma

INTRODUCTION The coexistence of potentially aggravating processes is common in asthmatics, particularly in patients with difficult control. The primary aim of this study is to ascertain whether comorbidity id more common in uncontrolled patients. As a secondary aim, we propose to evaluate the correlation between the asthma control test (ACT) and the fraction of exhaled nitric oxide (FENO). PATIENT AND METHODS A prospective, observational study comparing the function and clinical picture of two groups of asthmatics: controlled (ACT≥20) and uncontrolled (ACT<20). They were all assessed for, smoking, rhinosinusitis, obesity, anxiety, depression, vocal cord dysfunction, gastro-oesophageal reflux (GORD), allergic bronchopulmonary aspergillosis (ABPA), COPD and nasal polyps. RESULTS A total of 50 patients with controlled asthma and 102 with suboptimal control were included. The patients with an ACT≥20 had better lung function, less variation in PEF, less bronchial hyper-reactivity and lower FENO values. Comorbidities were found in 95% of the controlled asthmatics and in 97% of the uncontrolled. Only the presence of nasal polyps, GORD and ABPA was more frequent in the uncontrolled group. However, the simultaneous presence of 3 or more comorbidity factors was significantly more frequent in patients with sub-optimal control (P=0.01). There was no significant correlation between the FENO and the ACT values (rho=-0.08; P=0.32). CONCLUSIONS Aggravating comorbidities are more common in patients with sub-optimal control. There was no correlation between the FENO and the ACT values.

Effective Anti-immunoglobulin-E Antibody Treatment of a Patient With Allergic Bronchopulmonary Aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) develops as the result of a hypersensitivity reaction to the Aspergillus fungus and is associated with a form of asthma that is di cult to manage. Some studies indicate that inhaled corticosteroids achieve a good level of control in a substantial proportion of patients, with oral corticosteroids reserved for patients who fail to respond to the inhaled form. When treatment with oral corticosteroids has proven ineffective, the use of antifungal azoles has occasionally been successful. A recently reported case indicated that treatment with anti-immunoglobulin-E antibodies (omalizumab) could be effective when standard treatments failed. We describe the case of a man with lifethreatening, di cult-to-control asthma due to ABPA who experienced signiicant clinical and functional improvement in response to treatment with omalizumab. A 71-year-old man (a non-smoker) was diagnosed with asthma at the age of 50 years. He was initially treated with inhaled budesonide, salmeterol and terbutaline. This treatment regimen maintained forced expiratory volume in 1 second (FEV1) at normal levels, and treatment with oral corticosteroids was only necessary on a handful of occasions. When the patient was 62 years old, a decline in FEV1 to 58% of predicted was observed, although with no worsening of symptoms or increase in exacerbations. The option of prescribing oral corticosteroids was ruled out in favor of increasing the inhaled corticosteroid dose. From the age of 65 years, the patient experienced progressively worsening symptoms, with several exacerbations yearly (more than 3) that required admission to hospital, and, on 1 occasion, orotracheal intubation. By this time, FEV1 had declined to around 36% of predicted. When the patient was 68 years old, he was diagnosed with ABPA on the basis of the following indings: asthma, increased serum immunoglobulin-E levels (327 U/L), raised eosinophil count in blood (2200/μL), a skin prick test that was immediately positive for Aspergillus species, and proximal bronchiectasis as evidenced by a high-resolution computed tomography scan. Given the di culty in controlling the patient’s asthma (values of between 8 and 10 in the asthma control test of Vega et al) and the need for high doses of corticosteroids (delazacort, 30 mg/d), it was decided to treat him with 225 mg of omalizumab every fortnight. The symptoms were brought under control (with asthma control test scores consistently over 20), and the patient improved to the extent that, after the second dose of omalizumab, he only presented dyspnea in response to strenuous effort. In the 20 months in which the patient took omalizumab, he experienced only 1 exacerbation—6 months after commencing the treatment—that did not require admission to hospital; furthermore, symptoms continued to improve and FEV1 rose to 53% of predicted. By the end of the third month it was possible to discontinue treatment with delazacort. The pathogenesis of ABPA, which is an exaggerated reaction to Aspergillus antigens, is complex and has not yet been fully clariied. Nonetheless, the increase in immunoglobulin-E levels observed in these patients makes treatment with omalizumab a reasonable option a priori. In the literature we were only able to locate 1 similar case report, about a patient with cystic ibrosis and ABPA who showed clinical and functional improvement following administration of omalizumab. Our patient was experiencing progressive lung function loss, accompanied at a later stage by di cult-to-control symptoms and frequent admissions for severe asthma exacerbation. With a view to determining whether there was any concurrent process that might explain the progressive course of disease in this patient, we conducted a study that resulted in a diagnosis of ABPA on the basis of compliance with the 5 main ABPA criteria established by Rosenberg et al. Despite high doses of inhaled corticosteroids and veriication of correct inhalation technique, no appreciable improvement was achieved. A switch to treatment with oral delazacort also failed to produce a positive outcome. With few other therapeutic options available, we prescribed omalizumab on the basis that it might possibly beneit our patient. Clinical response by the end of the irst 2 months of treatment was very satisfactory, as relected in asthma control test scores of over 20. After 20 months, FEV1 had climbed from 36% to 53% of predicted–even though signiicant improvement in lung function occurs infrequently in patients treated with omalizumab according to a recent review. Our patient also had only 1 subsequent exacerbation, 6 months after commencing treatment with omalizumab; since this exacerbation responded to treatment with oral corticosteroids, hospitalization was not necessary. Treatment with delazacort was discontinued after 4 months. In sum, omalizumab may prove to be an effective treatment option for patients with ABPA and asthma that is refractory to treatment with inhaled and oral corticosteroids. It would be interesting to test omalizumab for this particular indication in an ad-hoc clinical trial.