The Importance of Reference Centers and Registries for Rare Diseases: The Example of Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is a rare and underdiagnosed disease that is associated with the development of liver disease in adults and children and pulmonary emphysema in adults. Several studies have shown that there is limited knowledge about the disease and its diagnosis among health care providers, and there is an important inequity in the access to specialized care and appropriate treatment across Europe. The European Commision and the European Respiratory Society (ERS) recommend that the care of patients with AATD must be organized in reference centers at national or regional levels. These reference centers must provide optimal clinical care in terms of adequate diagnostic techniques, such as phenotyping and genotyping, and ensure access to treatment according to guidelines. Reference centers should also provide continuous medical education for health care professionals, genetic counseling, collaboration with patient associations and promote collaborative research and clinical trials with new and existing treatments for the disease. These centers must have a registry of their activity and collaborate with large, international, multicenter registries, such as the European Alpha-1 antitrypsin Deficiency Research Collaboration (EARCO) international registry, which is endorsed by the ERS, and aims to recruit up to 3,000 patients over a period of three years and prospectively follow them to better understand the natural history of the disease and the impact of different treatments on outcomes in a real life setting. International collaboration and standardized collection of high-quality prospective data will provide new insights into the clinical manifestations and prognosis of AATD.

Impact of patient satisfaction with his or her inhaler on adherence and asthma control.

Background: Asthma guidelines recommend considering patient preferences for inhaler choice. However, few studies have assessed the impact of patient satisfaction with an inhaler on adherence and health outcomes. Objective: To assess the impact of patient satisfaction with an inhaler on adherence and health outcomes in asthma. Methods: In a cross-sectional, observational, multicenter study, 778 patients with moderate or severe asthma and who were treated with maintenance inhalers completed a number of scales and questionnaires: the Feeling of Satisfaction with Inhaler (FSI-10) questionnaire, the Treatment Satisfaction Questionnaire for Medication, the Test of Adherence to Inhalers (TAI), the Morisky-Green questionnaire, and the Asthma Control Test (ACT). Results: The study population was categorized according to a median FSI-10 score as high (49.4%) and low (50.6%) satisfaction with their inhaler. Logistic regression analysis showed that high specific satisfaction with an inhaler was associated with the younger age group (odds ratio [OR] 0.976 [95% confidence interval {CI} 0.965-0.987]); male gender (OR 1.725 [95% CI 1.187-2.507]); controlled asthma: ACT score ≥ 20 (OR 1.664 [95% CI 1.133-2.445]); high general satisfaction with treatment (OR 4.861 [95% CI 3.335-7.085]); high adherence to inhaler: TAI score ≥ 46 (OR 1.546 [95% CI 1.025-2.332]); nonsevere asthma (OR 1.056 [95% CI 0.648-1.721]); and no trouble with inhaler use (OR 0.401 [95% CI 0.174-0.922]). Conclusion: High patient satisfaction with an inhaler, irrespective of received medication, was related to adherence and asthma control. Our results pointed out the relevance of inhaler choice in inhaled therapy; these results could be useful for designing new strategies targeted to increase adherence in patients with asthma.

A proposal for the withdrawal of inhaled corticosteroids in the clinical practice of chronic obstructive pulmonary disease.

According to the current clinical practice guidelines for chronic obstructive pulmonary disease (COPD), the addition of inhaled corticosteroids (ICS) to long-acting ß2 agonist therapy is recommended in patients with moderate-to-severe disease and an increased risk of exacerbations. However, ICS are largely overprescribed in clinical practice, and most patients are unlikely to benefit from long-term ICS therapy.Evidence from recent randomized-controlled trials supports the hypothesis that ICS can be safely and effectively discontinued in patients with stable COPD and in whom ICS therapy may not be indicated, without detrimental effects on lung function, health status, or risk of exacerbations. This article summarizes the evidence supporting the discontinuation of ICS therapy, and proposes an algorithm for the implementation of ICS withdrawal in patients with COPD in clinical practice.Given the increased risk of potentially serious adverse effects and complications with ICS therapy (including pneumonia), the use of ICS should be limited to the minority of patients in whom the treatment effects outweigh the risks.

Impact of Applying the Global Lung Initiative Criteria for Airway Obstruction in GOLD Defined COPD Cohorts: The BODE and CHAIN Experience.

INTRODUCTION: The Global Lung Function Initiative (GLI) has proposed new criteria for airflow limitation (AL) and recommends using these to interpret spirometry. The objective of this study was to explore the impact of the application of the AL GLI criteria in two well characterized GOLD-defined COPD cohorts. METHODS: COPD patients from the BODE (n=360) and the COPD History Assessment In SpaiN (CHAIN) cohorts (n=722) were enrolled and followed. Age, gender, pack-years history, BMI, dyspnea, lung function measurements, exercise capacity, BODE index, history of exacerbations and survival were recorded. CT-detected comorbidities were registered in the BODE cohort. The proportion of subjects without AL by GLI criteria was determined in each cohort. The clinical, CT-detected comorbidity, and overall survival of these patients were evaluated. RESULTS: In total, 18% of the BODE and 15% of the CHAIN cohort did not meet GLI AL criteria. In the BODE and CHAIN cohorts respectively, these patients had a high clinical burden (BODE≥3: 9% and 20%; mMRC≥2: 16% and 45%; exacerbations in the previous year: 31% and 9%; 6MWD<350m: 15% and 19%, respectively), and a similar prevalence of CT-diagnosed comorbidities compared with those with GLI AL. They also had a higher rate of long-term mortality - 33% and 22% respectively. CONCLUSIONS: An important proportion of patients from 2 GOLD-defined COPD cohorts did not meet GLI AL criteria at enrolment, although they had a significant burden of disease. Caution must be taken when applying the GLI AL criteria in clinical practice.

Treatment of COPD by clinical phenotypes: putting old evidence into clinical practice.

The new Global Initiative for Chronic Obstructive Lung Disease update has moved the principles of treatment of stable chronic obstructive pulmonary disease (COPD) forward by including the concepts of symptoms and risks into the decision of therapy. However, no mention of the concept of clinical phenotypes is included. It is recognised that COPD is a very heterogeneous disease and not all patients respond to all drugs available for treatment. The identification of responders to therapies is crucial in chronic diseases to provide the most appropriate treatment and avoid unnecessary medications. The classically defined phenotypes of chronic bronchitis and emphysema, together with the newly described phenotypes of overlap COPD-asthma and frequent exacerbator, allow a simple classification of patients that share clinical characteristics and outcomes and, more importantly, similar responses to existing treatments. These clinical phenotypes can help clinicians identify patients that respond to specific pharmacological interventions. For example, frequent exacerbators are the only subjects with an indication for anti-inflammatory treatment in COPD. Among them, those with chronic bronchitis are the only candidates to receive phosphodiesterase-4 inhibitors. Patients with overlap COPD-asthma phenotype show an enhanced response to inhaled corticosteroids and infrequent exacerbators should only receive bronchodilators. These well-defined clinical phenotypes could potentially be incorporated into treatment guidelines.

A new approach to grading and treating COPD based on clinical phenotypes: summary of the Spanish COPD guidelines (GesEPOC).

After the development of the COPD Strategy of the National Health Service in Spain, all scientific societies, patient organisations, and central and regional governments formed a partnership to enhance care and research in COPD. At the same time, the Spanish Society of Pneumology and Thoracic Surgery (SEPAR) took the initiative to convene the various scientific societies involved in the National COPD Strategy and invited them to participate in the development of the new Spanish guidelines for COPD (Guía Española de la EPOC; GesEPOC). Probably the more innovative approach of GesEPOC is to base treatment of stable COPD on clinical phenotypes, a term which has become increasingly used in recent years to refer to the different clinical forms of COPD with different prognostic implications. The proposed phenotypes are: (A) infrequent exacerbators with either chronic bronchitis or emphysema; (B) overlap COPD-asthma; (C) frequent exacerbators with emphysema predominant; and (D) frequent exacerbators with chronic bronchitis predominant. The assessment of severity has also been updated with the incorporation of multidimensional indices. The severity of the obstruction, as measured by forced expiratory volume in 1 second, is essential but not sufficient. Multidimensional indices such as the BODE index have shown excellent prognostic value. If the 6-minute walking test is not performed routinely, its substitution by the frequency of exacerbations (BODEx index) provides similar prognostic properties. This proposal aims to achieve a more personalised management of COPD according to the clinical characteristics and multidimensional assessment of severity.

Impact of Early Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis: A multicenter Randomized Controlled Trial.

BACKGROUND AND OBJECTIVE: Forced vital capacity (FVC) less than 50% of predicted is one of the main parameters used for Non-Invasive Ventilation (NIV) initiation in Amyotrophic Lateral Sclerosis (ALS). Recent studies suggest that higher values of FVC could be considered as a threshold. The aim of this study is to evaluate whether early use of NIV improves the prognosis of ALS patients compared with standard initiation. METHODS: This is a randomized, parallel, multicenter, open-label, controlled clinical trial, with recruitment at the ALS outpatient multidisciplinary units of six Spanish hospitals. Patients were included when their FVC reached the 75% threshold and were randomized by computer, stratifying by center in an allocation ratio of 1:1 to Early NIV (FVC below 75%) or Standard NIV (FVC below 50%) initiation. The primary outcome was time to death or tracheostomy.Trial registration number ClinicalTrials.gov: NCT01641965. RESULTS: Between May 2012 and June 2014, 42 patients were randomized to two groups, 20 to Early NIV and 22 to Standard NIV initiation. We found differences in survival in favor of the intervention group: an incidence of mortality (2.68 [1.87-5.50] vs. 3.33 [1.34-4.80] person-months) and a median survival (25.2 vs. 19.4 months), although without reaching statistical significance (p = 0.267). CONCLUSIONS: This trial did not reach the primary endpoint of survival; nevertheless, it is the first Randomized Controlled Trial (RCT) to demonstrate the benefits of early NIV in slowing the decline of respiratory muscle strength and reducing adverse events. Although not all the results reached statistical significance, all the analyzed data favor early NIV. In addition, this study demonstrates good tolerance and compliance with early NIV without quality of sleep impairment. These data reinforce the early respiratory evaluation of ALS patients and NIV initiation with an FVC of around 75%.

[Spanish COPD Guidelines (GesEPOC): Pharmacological treatment of stable COPD]. / Guía Española de la EPOC (GesEPOC). Tratamiento farmacológico de la EPOC estable.

Recognizing the clinical heterogeneity of COPD suggests a specific therapeutic approach directed by the so-called clinical phenotypes of the disease. The Spanish COPD Guidelines (GesEPOC) is an initiative of SEPAR, which, together with the scientific societies involved in COPD patient care, and the Spanish Patient Forum, has developed these new clinical practice guidelines. This present article describes the severity classification and the pharmacological treatment of stable COPD. GesEPOC identifies four clinical phenotypes with differential treatment: non-exacerbator, mixed COPD-asthma, exacerbator with emphysema and exacerbator with chronic bronchitis. Pharmacological treatment of COPD is based on bronchodilation in addition to other drugs depending on the clinical phenotype and severity. Severity is established by the BODE/BODEx multidimensional scales. Severity can also be approximated by assessing airflow obstruction, dyspnea, level of physical activity and history of exacerbations. GesEPOC is a new, more individualized approach to COPD treatment according to the clinical characteristics of the patients.

Spanish COPD Guideline (GesEPOC) Update: Comorbidities, Self-Management and Palliative Care. / Actualización de la Guía Española de la EPOC (GesEPOC): comorbilidades, automanejo y cuidados paliativos.

The current health care models described in GesEPOC indicate the best way to make a correct diagnosis, the categorization of patients, the appropriate selection of the therapeutic strategy and the management and prevention of exacerbations. In addition, COPD involves several aspects that are crucial in an integrated approach to the health care of these patients. The evaluation of comorbidities in COPD patients represents a healthcare challenge. As part of a comprehensive assessment, the presence of comorbidities related to the clinical presentation, to some diagnostic technique or to some COPD-related treatments should be studied. Likewise, interventions on healthy lifestyle habits, adherence to complex treatments, developing skills to recognize the signs and symptoms of exacerbation, knowing what to do to prevent them and treat them within the framework of a self-management plan are also necessary. Finally, palliative care is one of the pillars in the comprehensive treatment of the COPD patient, seeking to prevent or treat the symptoms of a disease, the side effects of treatment, and the physical, psychological and social problems of patients and their caregivers. Therefore, the main objective of this palliative care is not to prolong life expectancy, but to improve its quality. This chapter of GesEPOC 2021 presents an update on the most important comorbidities, self-management strategies, and palliative care in COPD, and includes a recommendation on the use of opioids for the treatment of refractory dyspnea in COPD.

Spanish COPD Guidelines (GesEPOC 2021): Non-pharmacological Treatment Update. / Actualización 2021 de la Guía Española de la EPOC (GesEPOC). Tratamiento no farmacológico.

In addition to recommendations for pharmacological treatment stratified for risk and phenotype, the new 2021 edition of the Spanish COPD Guidelines (GesEPOC 2021) proposes a personalized approach to treatable traits, defined as a characteristic (clinical, physiological, or biological) that can be identified by diagnostic tests or biomarkers, for which a specific treatment is available. Some treatable traits, such as malnutrition, sedentarism, emphysema or respiratory failure, can be treated with non-pharmacological therapies, and this was not covered in detail in the guidelines. This section of GesEPOC 2021 includes a narrative update with recommendations on dietary treatment, physical activity, respiratory rehabilitation, oxygen therapy, non-invasive ventilation, volume reduction, and lung transplantation. A PICO question with recommendations on the use of supplemental oxygen during exercise in COPD patients without severe hypoxemia is also included.

Spanish COPD Guidelines (GesEPOC) 2021: Updated Pharmacological treatment of stable COPD. / Actualización 2021 de la Guía Española de la EPOC (GesEPOC). Tratamiento farmacológico de la EPOC estable.

The Spanish COPD Guidelines (GesEPOC) were first published in 2012, and since then have undergone a series of updates incorporating new evidence on the diagnosis and treatment of COPD. GesEPOC was drawn up in partnership with scientific societies involved in the treatment of COPD and the Spanish Patients' Forum. Their recommendations are based on an evaluation of the evidence using GRADE methodology, and a narrative description of the evidence in areas in which GRADE cannot be applied. In this article, we summarize the recommendations on the pharmacological treatment of stable COPD based on 9 PICO questions. COPD treatment is a 4-step process: 1) diagnosis, 2) determination of the risk level, 3) initial and subsequent inhaled therapy, and 4) identification and management of treatable traits. For the selection of inhaled therapy, high-risk patients are divided into 3 phenotypes: non-exacerbator, eosinophilic exacerbator, and non-eosinophilic exacerbator. Some treatable traits are general and should be investigated in all patients, such as smoking or inhalation technique, while others affect severe patients in particular, such as chronic hypoxemia and chronic bronchial infection. COPD treatment is based on long-acting bronchodilators with single agents or in combination, depending on the patient's risk level. Eosinophilic exacerbators must receive inhaled corticosteroids, while non-eosinophilic exacerbators require a more detailed evaluation to choose the best therapeutic option. The new GesEPOC also includes recommendations on the withdrawal of inhaled corticosteroids and on indications for alpha-1 antitrypsin treatment. GesEPOC offers a more individualized approach to COPD treatment tailored according to the clinical characteristics of patients and their level of complexity.

Spanish COPD Guidelines (GesEPOC) 2021 Update Diagnosis and Treatment of COPD Exacerbation Syndrome. / Actualización 2021 de la guía española de la EPOC (GesEPOC). Diagnóstico y tratamiento del síndrome de agudización de la EPOC.

This article details the GesEPOC 2021 recommendations on the diagnosis and treatment of COPD exacerbation syndrome (CES). The guidelines propose a definition-based syndromic approach, a new classification of severity, and the recognition of different treatable traits (TT), representing a new step toward personalized medicine. The evidence is evaluated using GRADE methodology, with the incorporation of 6 new PICO questions. The diagnostic process comprises four stages: 1) establish a diagnosis of CES, 2) assess the severity of the episode, 3) identify the trigger, and 4) address TTs. This diagnostic process differentiates an outpatient approach, that recommends the inclusion of a basic battery of tests, from a more comprehensive hospital approach, that includes the study of different biomarkers and imaging tests. Bronchodilator treatment for immediate relief of symptoms is considered essential for all patients, while the use of antibiotics, systemic corticosteroids, oxygen therapy, and assisted ventilation and the treatment of comorbidities will vary depending on severity and possible TTs. The use of antibiotics will be indicated particularly if sputum color changes, when ventilatory assistance is required, in cases involving pneumonia, and in patients with elevated C-reactive protein (≥ 20 mg/L). Systemic corticosteroids are recommended in CES that requires admission and are suggested in moderate CES. These drugs are more effective in patients with blood eosinophil counts ≥ 300 cells/mm3. Acute-phase non-invasive mechanical ventilation is specified primarily for patients with CES who develop respiratory acidosis despite initial treatment.

[Translated article] Spanish COPD Guidelines (GesEPOC) 2021 Update. Diagnosis and Treatment of COPD Exacerbation Syndrome.

This article details the GesEPOC 2021 recommendations on the diagnosis and treatment of COPD exacerbation syndrome (CES). The guidelines propose a definition-based syndromic approach, a new classification of severity, and the recognition of different treatable traits (TT), representing a new step toward personalized medicine. The evidence is evaluated using GRADE methodology, with the incorporation of 6 new PICO questions. The diagnostic process comprises four stages: 1) establish a diagnosis of CES, 2) assess the severity of the episode, 3) identify the trigger, and 4) address TTs. This diagnostic process differentiates an outpatient approach, that recommends the inclusion of a basic battery of tests, from a more comprehensive hospital approach, that includes the study of different biomarkers and imaging tests. Bronchodilator treatment for immediate relief of symptoms is considered essential for all patients, while the use of antibiotics, systemic corticosteroids, oxygen therapy, and assisted ventilation and the treatment of comorbidities will vary depending on severity and possible TTs. The use of antibiotics will be indicated particularly if sputum color changes, when ventilatory assistance is required, in cases involving pneumonia, and in patients with elevated C-reactive protein (≥ 20 mg/L). Systemic corticosteroids are recommended in CES that requires admission and are suggested in moderate CES. These drugs are more effective in patients with blood eosinophil counts ≥ 300 cells/mm3. Acute-phase non-invasive mechanical ventilation is specified primarily for patients with CES who develop respiratory acidosis despite initial treatment.

Noninvasive electrical stimulation of oropharyngeal muscles in obstructive sleep apnea.

Introduction: Continuous positive airway pressure (CPAP) therapy remains the standard treatment for obstructive sleep apnea. However, its proven effect is useless if the patient does not tolerate the treatment. The electrical stimulation approach has been investigated for several decades now and it seems that the implantable devices for invasive electrical stimulation of hypoglossal nerve are viewed as effective with some of them already approved for human use.Areas covered: in this review, we intent to summarize the existing records of noninvasive stimulation in sleep apnea to make the scientific community aware of the details before deciding on its future. We believe that this is a battle still to fight and more could be done bearing in mind the safety of this method.Expertopinion: noninvasive electrical stimulation has been left behind based on few, small and inconsistent studies using different stimulation parameters. These studies are difficult to compare and to draw conclusions.Electrical stimulation is a field for research in the treatment of obstructive sleep apnea, with many aspects still to be discovered, and which may become a therapeutic alternative to the use of CPAP in certain patients.

Utility of Transient Elastography for the Screening of Liver Disease in Patients with Alpha1-Antitrypsin Deficiency.

Screening of liver disease in alpha-1 antitrypsin deficiency (AATD) is usually carried out with liver enzymes, with low sensitivity. We conducted a multicenter cross-sectional study aiming to describe the utility of transient elastography for the identification of liver disease in patients with AATD. A total of 148 AATD patients were included. Among these, 54.7% were Pi*ZZ and 45.3% were heterozygous for the Z allele. Between 4.9% and 16.5% of patients had abnormal liver enzymes, without differences among genotypes. Liver stiffness measurement (LSM) was significantly higher in Pi*ZZ individuals than in heterozygous Z (5.6 vs. 4.6 kPa; p = 0.001). In total, in 8 (5%) individuals LSM was >7.5 kPa, considered significant liver fibrosis, and ≥10 kPa in 3 (1.9%) all being Pi*ZZ. Elevated liver enzymes were more frequently observed in patients with LSM > 7.5 kPa, but in 5 out of 8 of these patients all liver enzymes were within normal range. In patients with AATD, the presence of abnormal liver enzymes is frequent; however, most of these patients do not present significant liver fibrosis. Transient elastography can help to identify patients with liver fibrosis even with normal liver enzymes and should be performed in all Z-allele carriers to screen for liver disease.

Results of a Diagnostic Procedure Based on Multiplex Technology on Dried Blood Spots and Buccal Swabs for Subjects With Suspected Alpha1 Antitrypsin Deficiency.

INTRODUCTION: The objective of this analysis was the evaluation of a new national circuit used for diagnosing alpha1 antitrypsin deficiency (AATD) based on multiplex technology using online registration and mail posted samples from dried blood spots (DBS) and buccal swabs. METHODS: This is an observational, ongoing study conducted in Spain since March 2018. Samples are coded on a web platform and sent by postal mail to the central laboratory. Allele-specific genotyping for the 14 most common mutations was done with the Luminex 200 Instrument System. Gene sequencing was done if none of the mutations were found and the AAT serum level was <60mg/dl, or by request from the clinician in charge. RESULTS: At the time of the present report, 5803 (92.9%) samples were processed, 4984 (85.9%) from buccal swab and 819 (14.1%) from DBS. The prevalence of the frequent allele combinations were: MS 19.0%, MZ 14.4%, SS 2.9%, SZ 3.7%, and ZZ: 1.4%. Globally, Z carriers represented 20.0% and S carriers 26.6% of this population, with differences seen between regions. 209 (3.6%) were identified carrying rare alleles, 12 (0.2%) carrying null alleles and 14 (0.3%) new mutations were described. Respiratory diseases other than COPD, including poorly controlled asthma or bronchiectasis, also presented AATD mutations. CONCLUSIONS: The availability of a diagnostic system based on the simultaneous testing of 14 genetic variants from buccal swabs or DBS sent by postal mail and with web registration has proven to be useful, and the system can improve the timely diagnosis of AATD.

Off-label use of inhaled bronchodilators in hospitalised patients in Spain: a multicentre observational study.

BACKGROUND: Off-label prescription of inhaled bronchodilators (IB) is frequent, despite the fact that they can be ineffective and increase avoidable healthcare costs. OBJECTIVE: To analyse the frequency of off-label prescription of IB in hospitalised patients. Indications and level of evidence, involved drugs, medical specialties prescribing off-label IB and patients' adherence to IBs were also evaluated. METHOD: A descriptive, observational, cross-sectional study was performed in four tertiary hospitals in Spain. The main outcome measure was the number of patients prescribed off-label IBs. Prescriptions were checked against the European Medicines Agency-approved indications. The level of evidence supporting off-label prescription of IBs (according to MICROMEDEX 2.0) was also analysed. Patients were interviewed to test differences (off-label vs on-label) in adherence and knowledge about their inhaled therapy. RESULTS: 217 patients were prescribed IBs, 92 of whom were givend off-label IBs (54.7% men, mean age 73.9±12.9 years). The most common off-label prescriptions for IBs were: unspecified dyspnoea (not related to COPD or asthma) (27.2%), respiratory infections (23.9%) and heart failure (22.8%). 76.8% of patients did not have evidence supporting them. Beta2-agonist+corticosteroids and anticholinergics were most commonly prescribed off-label. Internal Medicine was the main medical specialty involved. There were no differences between off-label and on-label users in terms of patients' knowledge about treatment and adherence. CONCLUSION: Off-label indications for IBs are common in hospitalised patients and are generally indicated without scientific support. Dyspnoea not related to COPD or asthma, respiratory infections and heart failure were the main off-label indications, most frequently treated with anticholinergics and beta2-agonists+corticosteroids, for which their efficacy and safety has not been proved. Our results show that prescribing needs to be improved to follow the evidence that exists. Moreover, further research focused on off-label indications is needed to clarify whether they are effective, safe and cost-effective.

Natural Course of the Diffusing Capacity of the Lungs for Carbon Monoxide in COPD: Importance of Sex.

BACKGROUND: The value of the single-breath diffusing capacity of the lungs for carbon monoxide (Dlco) relates to outcomes for patients with COPD. However, little is known about the natural course of Dlco over time, intersubject variability, and factors that may influence Dlco progression. RESEARCH QUESTION: What is the natural course of Dlco in patients with COPD over time, and which other factors, including sex differences, could influence this progression? STUDY DESIGN AND METHODS: We phenotyped 602 smokers (women, 33%), of whom 506 (84%) had COPD and 96 (16%) had no airflow limitation. Lung function, including Dlco, was monitored annually over 5 years. A random coefficients model was used to evaluate Dlco changes over time. RESULTS: The mean (± SE) yearly decline in Dlco % in patients with COPD was 1.34% ± 0.015%/y. This was steeper compared with non-COPD control subjects (0.04% ± 0.032%/y; P = .004). Sixteen percent of the patients with COPD, vs 4.3% of the control subjects, had a statistically significant Dlco % slope annual decline (4.14%/y). At baseline, women with COPD had lower Dlco values (11.37% ± 2.27%; P < .001) in spite of a higher FEV1 % than men. Compared with men, women with COPD had a steeper Dlco annual decline of 0.89% ± 0.42%/y (P = .039). INTERPRETATION: Patients with COPD have an accelerated decline in Dlco compared with smokers without the disease. However, the decline is slow, and a testing interval of 3 to 4 years may be clinically informative. The lower and more rapid decline in Dlco values in women, compared with men, suggests a differential impact of sex in gas exchange function. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01122758; URL: www.clinicaltrials.gov.

Prevalence of modifiable factors limiting treatment efficacy of poorly controlled asthma patients: EFIMERA observational study.

Several modifiable factors leading to poor asthma control have been described. We aimed to determine the proportion of patients with inadequate treatment, adherence to it, or critical mistakes with inhaler technique, and their impact on asthma control. We conducted a cross-sectional multicenter observational study including asthma patients referred from primary to specialist care for the first time. Data collected were adequate prescription according to guidelines, treatment adherence, and disease control. Of the 1682 patients (age 45 ± 17 years, 64.6% men), 35.9% showed inadequate prescription, 76.8% low adherence, and 17% critical mistakes with inhaler technique, with significantly less critical mistakes among Easyhaler users versus other dry powder inhaler users (10.3 versus 18.4%; p < 0.05). Factors related to bad asthma control were inadequate prescription (OR: 3.65), non-adherence to treatment (OR: 1.8), and inhaler misuse (OR: 3.03). A higher number of risk factors were associated with a higher probability of having badly controlled asthma.