Miriam Barrecheguren

The asthma–chronic obstructive pulmonary disease overlap syndrome (acos): opportunities and challenges

Purpose of review Some individuals share characteristics of asthma and chronic obstructive pulmonary disease (COPD). The asthma–COPD overlap syndrome (ACOS) has been defined as symptoms of increased variability of airflow in association with an incompletely reversible airflow obstruction. In this review, we present the latest findings in the diagnosis, characterization and management of ACOS. Recent findings Around 15–20% of COPD patients may have an ACOS. Patients with ACOS are characterized by increased reversibility of airflow obstruction, eosinophilic bronchial and systemic inflammation, and increased response to inhaled corticosteroids, compared with the remaining patients with COPD. Patients with ACOS have more frequent exacerbations, more wheezing and dyspnoea, but similar cough and sputum production compared with COPD. Summary The relevance of the ACOS is to identify patients with COPD who may have underlying eosinophilic inflammation that responds to inhaled corticosteroids. So far, the previous diagnosis of asthma in a patient with COPD is the more reliable criterion for ACOS. Ongoing studies will clarify if concentrations of blood eosinophils may be useful to identify this subgroup of patients with COPD. If this is the case, the interest of ACOS may shift to that of eosinophilic COPD, which is easier to diagnose and has clear therapeutic implications.

Is a previous diagnosis of asthma a reliable criterion for asthma–COPD overlap syndrome in a patient with COPD?

Background Some patients share characteristics of both COPD and asthma. As yet, there is no gold standard to identify patients with the so-called asthma–COPD overlap syndrome (ACOS). Objective To describe the differences between ACOS patients and the remaining COPD patients, and to compare the clinical characteristics of patients diagnosed with ACOS by two different criteria: previous diagnosis of asthma before the age of 40 years; and the diagnostic criteria of the Spanish guidelines of COPD. Methods Multicenter, observational, cross-sectional study performed in 3,125 COPD patients recruited in primary care and specialized outpatient clinics. Patients with COPD and a history of asthma before the age of 40 years were diagnosed with ACOS and compared to the remaining COPD patients. Subsequently, ACOS patients were subdivided based on whether they fulfilled the Spanish guidelines of the COPD diagnostic criteria or not, and they were compared. Results ACOS was diagnosed in 15.9% of the patients. These patients had different basal characteristics compared to the remaining COPD patients, including a higher frequency of women and more exacerbations despite lower tobacco exposure and better lung function. They were more likely to have features of asthma, such as a positive bronchodilator test, higher peripheral eosinophilia, and higher total immunoglobulin E. Within the ACOS group, only one-third fulfilled the diagnostic criteria of the Spanish guidelines of COPD; these individuals were not significantly different from the remaining ACOS patients, except for having more exacerbations and poorer lung function. Conclusion ACOS patients diagnosed on the basis of a previous diagnosis of asthma differed from the remaining COPD patients, but they were similar to ACOS patients diagnosed according to more restrictive criteria, suggesting that a history of asthma before the age of 40 years could be a useful criterion to suspect ACOS in a patient with COPD.

Frequency and characteristics of different clinical phenotypes of chronic obstructive pulmonary disease.

SETTING Clinical phenotypes of chronic obstructive pulmonary disease (COPD) identify patients with common characteristics. OBJECTIVES To investigate the distribution of four different COPD phenotypes: non-exacerbators, patients with asthma-COPD overlap syndrome (ACOS), exacerbators with chronic bronchitis and those without, we analysed the impact of COPD on quality of life (HRQoL), and on anxiety and depression in these phenotypes. DESIGN Observational, multicentre study conducted among 3125 COPD patients recruited from out-patient clinics in Barcelona, Spain. Phenotyping was performed based on the clinical information available. The COPD Assessment Test and EuroQoL-5 Dimensions questionnaire were used to evaluate HRQoL; patient mood was evaluated using the Hospital Anxiety and Depression Scale (HADS). RESULTS The distribution of phenotypes was as follows: 60.6% non-exacerbators, 15.9% ACOS patients, 19.3% exacerbators with chronic bronchitis and 4.3% exacerbators without chronic bronchitis. Non-exacerbators had milder COPD, whereas exacerbators presented with the most severe disease, with little difference between those with and those without chronic bronchitis. ACOS patients were more frequently female with better lung function, but more impaired HRQoL and greater anxiety and depression, than non-exacerbators. CONCLUSIONS Almost two thirds of COPD patients are non-exacerbators, and 15.9% have ACOS. Different phenotypes showed different demographic and clinical characteristics as well as impact on HRQoL and mood.

The CAT (COPD Assessment Test) questionnaire as a predictor of the evolution of severe COPD exacerbations.

INTRODUCTION Since exacerbations of chronic obstructive pulmonary disease (COPD) cause both a great impact on the progression of the disease and generate high health expenditures, there is a need to develop tools to evaluate their prognosis. METHOD Multicenter, observational, prospective study that evaluated the prognostic utility of the COPD Assessment Test (CAT) in severe exacerbations of COPD. Anthropometric and clinical variables were analyzed: smoking, history of exacerbations during the previous year, drug treatment, degree of baseline dyspnea, comorbidities; laboratory variables at admission (complete blood count, arterial blood gas and biochemistry) and CAT scores in the first 24 h of admission, on the third day, at discharge and at 3 months. RESULTS We evaluated 106 patients (91 males) with a mean age of 71.1 (SD 9.8 years), mean FEV1 45.2% (14.7%) and average CAT score at admission of 24.7 points (7.1). At three months after discharge, treatment failure was observed in 39 (36.8%) patients: 14 (13.2%) presented an exacerbation without the need for hospital admission, 22 were readmitted (20.8%) and 3 (2.8%) died during follow-up. The three factors associated with increased risk of failure were a reduction less than 4 units in the CAT at discharge compared to admission, lower hemoglobin levels and treatment with domiciliary oxygen. CONCLUSIONS A change of ≤4 points in the CAT score at discharge compared to that obtained at admission due to a severe exacerbation of COPD, helps to predict therapeutic failure such as a new exacerbation, readmission or death in the subsequent three months.

Diagnosis of alpha-1 antitrypsin deficiency: a population-based study

Introduction Alpha-1 antitrypsin deficiency (AATD) remains an underdiagnosed condition despite initiatives developed to increase awareness. The objective was to describe the current situation of the diagnosis of AATD in primary care (PC) in Catalonia, Spain. Methods We performed a population-based study with data from the Information System for Development in Research in Primary Care, a population database that contains information of 5.8 million inhabitants (80% of the population of Catalonia). We collected the number of alpha-1 antitrypsin (AAT) determinations performed in the PC in two periods (2007–2008 and 2010–2011) and described the characteristics of the individuals tested. Results A total of 12,409 AAT determinations were performed (5,559 in 2007–2008 and 6,850 in 2010–2011), with 10.7% of them in children. As a possible indication for AAT determination, 28.9% adults and 29.4% children had a previous diagnosis of a disease related to AATD; transaminase levels were above normal in 17.7% of children and 47.1% of adults. In total, 663 (5.3%) individuals had intermediate AATD (50–100 mg/dL), 24 (0.2%) individuals had a severe deficiency (<50 mg/dL), with a prevalence of 0.19 cases of severe deficiency per 100 determinations. Nine (41%) of the adults with severe deficiency had a previous diagnosis of COPD/emphysema, and four (16.7%) were diagnosed with COPD within 6 months. Conclusion The number of AAT determinations in the PC is low in relation to the prevalence of COPD but increased slightly along the study period. The indication to perform the test is not always clear, and patients detected with deficiency are not always referred to a specialist.

Application of a diagnostic algorithm for the rare deficient variant Mmalton of alpha-1-antitrypsin deficiency: a new approach

Background and objectives Alpha-1-antitrypsin deficiency (AATD) is associated with a high risk for the development of early-onset emphysema and liver disease. A large majority of subjects with severe AATD carry the ZZ genotype, which can be easily detected. Another rare pathologic variant, the Mmalton allele, causes a deficiency similar to that of the Z variant, but it is not easily recognizable and its detection seems to be underestimated. Therefore, we have included a rapid allele-specific genotyping assay for the detection of the Mmalton variant in the diagnostic algorithm of AATD used in our laboratory. The objective of this study was to test the usefulness of this new algorithm for Mmalton detection. Materials and methods We performed a retrospective revision of all AATD determinations carried out in our laboratory over 2 years using the new diagnostic algorithm. Samples with a phenotype showing one or two M alleles and AAT levels discordant with that phenotype were analyzed using the Mmalton allele-specific genotyping assay. Results We detected 49 samples with discordant AAT levels; 44 had the MM and five the MS phenotype. In nine of these samples, a single rare Mmalton variant was detected. During the study period, two family screenings were performed and four additional Mmalton variants were identified. Conclusion The incorporation of the Mmalton allele-specific genotyping assay in the diagnostic algorithm of AATD resulted in a faster and cheaper method to detect this allele and avoided a significant delay in diagnosis when a sequencing assay was required. This methodology can be adapted to other rare variants. Standardized algorithms are required to obtain conclusive data of the real incidence of rare AAT alleles in each region.

Rapid detection of Mmalton α1-antitrypsin deficiency allele by real-time PCR and melting curves in whole blood, serum and dried blood spot samples.

Abstract Background: α1-Antitrypsin deficiency (AATD) is an autosomal codominant disorder associated with a high risk of developing lung and liver disease. The most common deficient alleles are known as Z and S. However, another deficient variant, called Mmalton, which causes a deficiency similar to variant Z, is considered to be the second cause of severe AATD in Spain. Nevertheless, the Mmalton allele is not recognizable by usual diagnostic techniques and therefore, its real prevalence is underestimated. We describe a rapid real-time PCR and melting curves assay designed for the detection of Mmalton AATD. Methods: We tested the applicability of this new technique for the identification of the Mmalton allele in AATD screening using whole blood, dried blood spot (DBS) and serum samples. Mmalton heterozygote and homozygote samples and samples without this allele were included in the study. Results: This new assay is able to detect homozygous and heterozygous genotypes in the same reaction and in a single step, giving matching results with those obtained by SERPINA1 gene sequencing. Conclusions: This technology is optimal for working with small amounts of DNA, such as in DBS and even with residual DNA present in serum samples, allowing improvement in routine algorithms of AATD diagnosis or large-scale screening. This method will be useful for obtaining more in depth knowledge of the real incidence of the Mmalton variant.

Self-reported daily walking time in COPD: relationship with relevant clinical and functional characteristics

Background Quantifying physical activity in chronic obstructive pulmonary disease (COPD) is important as physical inactivity is related to poor health outcomes. This study analyzed the relationship between patients’ self-reported daily walking time and relevant characteristics related to COPD severity. Methods Pooled analysis was performed on data from four observational studies on which daily walking time was gathered from a personal interview. Patients were classified as physically inactive if walking time was <30 min/day. Walking times were described and compared according to several markers of disease severity. Results The mean daily walking time of 5,969 patients was 66 (standard deviation [SD] 47) min/day; 893 (15%) patients were inactive. A linear dose–response relationship was observed between walking time and the modified Medical Research Council (mMRC) dyspnea score, admissions, COPD assessment test (CAT), body mass index, airway obstruction, dyspnea, exacerbation (BODEx) index, and Charlson index (P<0.001). Daily walking times were lower in patients classified as Global Initiative for Chronic Obstructive Lung Disease (GOLD) B and D (P<0.001). Often, inactive patients had mMRC or Charlson index >3, post-bronchodilator forced expiratory volume in the first second <30% predicted, at least one hospitalization for COPD, classified as GOLD B or D, BODEx >4, and CAT score >30. Conclusion Lower self-reported walking times are related to worse markers of disease severity in COPD.

Should Patients Switched from D to B in the GOLD 2017 Classification be Discontinued from Inhaled Corticosteroids

ABSTRACT Inhaled corticosteroids (ICSs) are the cornerstone of the treatment of asthma, but their role in COPD is limited. Several guidelines recommend their use in patients with severe airflow limitation, frequent exacerbations and asthma-COPD overlap (ACO), while the previous GOLD document recommended ICS for patients with high risk of exacerbations and a high level of symptoms (group D). Following the changes in the GOLD document 2017 update, in which impaired lung function is no longer considered as a determinant of exacerbation risk, a high number of COPD patients can now be labeled as group B (low risk of exacerbations and high level of symptoms) instead of D, and hence, no longer fulfill the indication for ICS. Since long-term therapy with ICS can entail secondary effects, the withdrawal of this treatment should be considered in this group of patients. In this article, we summarize the evidence for discontinuation of ICS in this subgroup of patients and provide suggestions for clinicians on the appropriate use on ICS in patients moving from D to B.

¿Cómo podemos identificar a los pacientes con fenotipo mixto asma-EPOC (ACOS) en la práctica clínica?

En una reciente reunión de consenso en la que participaron 6 especialistas españoles, el 85% opinaba que existía lo que llaamos el fenotipo mixto EPOC-asma o por el inglés asthma-COPD verlap syndrome (ACOS). Sin embargo, hubo un menor consenso obre qué características definían este fenotipo, y cómo se podía dentificar en la práctica clínica habitual1. La necesidad de ponernos de acuerdo en lo que significa el ACOS a originó una primera reunión de consenso destinada a definir el COS como un fenotipo de la EPOC. Esta necesidad surgió de la cumulación de evidencia de que existen pacientes con EPOC que resentan características asmáticas, y que esto implica una mejor espuesta al tratamiento con corticosteroides inhalados (ICS). En sta reunión se consensuaron una serie de criterios mayores y enores para el diagnóstico de ACOS2; sin embargo, estudios poseriores han demostrado que estos criterios son excesivamente estrictivos, y que su aplicación identifica tan solo una pequeña arte de los pacientes que pueden presentar un ACOS3. Si los criterios del consenso español son excesivamente restricivos, los criterios recientes de la Global Initiative for Asthma (GINA) la Global Initiative for Obstructive Lung Disease (GOLD) resultan mprecisos y ambiguos. Se trata de una lista de características sociadas al asma, y otra lista de características asociadas a la POC, para que el médico marque con una cruz aquellas que resenta su paciente, y si el número de cruces es similar en mbas listas es que probablemente estemos ante un ACOS4. No e indica cuántas cruces son necesarias, y todas ellas tienen la isma importancia, a pesar de que no todas las características ienen el mismo valor a la hora de identificar el asma o la EPOC. Si olvemos a la opinión de los participantes en el consenso español, os criterios diagnósticos de ACOS más relevantes fueron para un 8% el diagnóstico previo de asma en un paciente con EPOC, para