Cecilia López-Ramírez

Exacerbations or complications? Redefining the concepts in COPD.

To the Editor: Chronic inflammatory diseases such as inflammatory bowel disease, multiple sclerosis or rheumatoid arthritis are characterised by continuing inflammation, which is frequently of unknown origin. From a pathophysiological perspective, all of these conditions share common features including the presence of organ-specific inflammation, the occurrence of a systemic inflammatory response, and episodic peaks in inflammation. The latter may lead to an increase in the severity of the disease or its signs and symptoms (known as bouts, crisis or exacerbations), ultimately requiring treatment modifications. Exacerbations are deemed to be an intrinsic feature of chronic inflammatory disorders and part of their natural history (1–3). In contrast, patients with chronic inflammatory diseases may frequently experience comorbid transient acute disorders (generally of known origin) that may significantly complicate the clinical picture as well. Despite their impact on the total inflammatory load, such episodes are not necessarily considered part of the natural history of the disease and are referred to as complications. Some examples of complications include the occurrence of acute diarrhoea in patients with inflammatory bowel disease, cerebrovascular events in patients with multiple sclerosis, and septic arthritis in patients with rheumatoid arthritis. The differentiation between exacerbations and complications in patients with chronic inflammatory diseases is clinically relevant because of therapeutic implications and potential prognostic impact. Chronic obstructive pulmonary disease (COPD) shares several features with other chronic inflammatory diseases. Although COPD undoubtedly has a multifaceted aetiology, tobacco use is widely considered to be its major risk factor. However, the higher inflammatory load observed in COPD patients as compared with non-COPD smokers has no obvious origin. As in other chronic inflammatory conditions, COPD patients may experience transient increases in symptoms associated with a higher inflammatory load. Although such episodes are generally known as exacerbations, controversy still exists on their exact definition as well as their differentiation from other acute respiratory conditions that may complicate COPD. According to international guidelines, a COPD exacerbation is defined as ‘an acute event characterised by a worsening of the patient’s respiratory symptoms that is beyond day to day variations and leads to a change in medication’ (4). Despite its wide use, there has been considerable debate as to the definition of COPD exacerbations (5). For example, it is well known that COPD patients may suffer from acute pulmonary embolism (PE). If the traditional definition is followed, PE should be considered as an exacerbation of COPD as it would lead to a sustained worsening of symptoms beyond normal day to day variations and may warrant a change in medication. However, such worsening is clearly unrelated to COPD pathophysiology because PE is a distinct clinical entity with its own specific risk factors (6). In this scenario, it is conceivable that PE episodes should be considered as a complication – rather than an exacerbation – of COPD. Conversely, it should be also acknowledged that PE may also be a cause of COPD exacerbations (7), generating further classification controversy. Another similar example is provided by community acquired pneumonia (CAP). Patients with COPD are known to be at an increased risk for developing acute CAP, a condition which can in turn lead to symptoms worsening and need of treatment changes. Although CAP may fulfil the definition of an exacerbation (8), it is an infectious process that has no obvious correlation with COPD pathophysiology. One may also argue that episodes of acute infectious bronchitis are generally considered as COPD exacerbations with antibiotic therapy assuming a prominent role (9). Although CAP and acute bronchitis differ in terms of infection sites, the contention that a bronchial infection should be considered an exacerbation whereas a parenchymal infection should not is not clear or doesn’t seem to be coherent. Moreover, as the presence of lung condensations is frequently reported in patients discharged with a diagnosis of COPD exacerbations (10), the confusion will escalate. Another interesting example is provided by inhaled steroids, which may decrease the number of exacerbations but can in turn increase the number of lung infections (11). Consequently, infections and COPD should be considered as comorbid conditions (12). Beyond semantics, an infective cause of COPD worsening should guide the clinician towards an appropriate targeted therapy. As in other chronic inflammatory conditions, it is paramount to make a clear distinction between COPD exacerbations and complications. In this scenario, we propose that any of these acute events that is not directly related to COPD pathophysiology should be considered as a complication. By contrast, an exacerbation should indicate any episode of increased bronchial inflammation which reflects these respiratory inflammatory bouts associated with the natural expression of the disease.

Evaluation of the COPD Assessment Test and GOLD patient types: a cross-sectional analysis

Background The COPD Assessment Test (CAT) has been recently developed to quantify COPD impact in routine practice. However, no relationship with other measures in the Global Initiative for Obstructive Lung Disease (GOLD) strategy has been evaluated. The present study aimed to evaluate the relationship of the CAT with other GOLD multidimensional axes, patient types, and the number of comorbidities. Methods This was a cross-sectional analysis of the Clinical presentation, diagnosis, and course of chronic obstructive pulmonary disease (On-Sint) study. The CAT score was administered to all participants at the inclusion visit. A GOLD 2011 strategy consisting of modified Medical Research Council scale (MRC) scores was devised to study the relationship between the CAT, and GOLD 2011 axes and patient types. The relationship with comorbidities was assessed using the Charlson comorbidity index, grouped as zero, one to two, and three or more. Results The CAT questionnaire was completed by 1,212 patients with COPD. The CAT maintained a relationship with all the three axes, with a ceiling effect for dyspnea and no distinction between mild and moderate functional impairment. The CAT score increased across GOLD 2011 patient types A–D, with similar scores for types B and C. Within each GOLD 2011 patient type, there was a considerably wide distribution of CAT values. Conclusion Our study indicates a correlation between CAT and the GOLD 2011 classification axes as well as the number of comorbidities. The CAT score can help clinicians, as a complementary tool to evaluate patients with COPD within the different GOLD patient types.

Cigarette Smoke Decreases the Maturation of Lung Myeloid Dendritic Cells.

Background Conflicting data exist on the role of pulmonary dendritic cells (DCs) and their maturation in patients with chronic obstructive pulmonary disease (COPD). Herein, we investigated whether disease severity and smoking status could affect the distribution and maturation of DCs in lung tissues of patients undergoing elective pneumectomy or lobectomy for suspected primary lung cancer. Materials and Methods A total of 75 consecutive patients were included. Spirometry testing was used to identify COPD. Lung parenchyma sections anatomically distant from the primary lesion were examined. We used flow cytometry to identify different DCs subtypes—including BDCA1-positive myeloid DCs (mDCs), BDCA3-positive mDCs, and plasmacytoid DCs (pDCs)—and determine their maturation markers (CD40, CD80, CD83, and CD86) in all participants. We also identified follicular DCs (fDCs), Langerhans DCs (LDCs), and pDCs in 42 patients by immunohistochemistry. Results COPD was diagnosed in 43 patients (16 current smokers and 27 former smokers), whereas the remaining 32 subjects were classified as non-COPD (11 current smokers, 13 former smokers, and 8 never smokers). The number and maturation of DCs did not differ significantly between COPD and non-COPD patients. However, the results of flow cytometry indicated that maturation markers CD40 and CD83 of BDCA1-positive mDCs were significantly decreased in smokers than in non-smokers (P = 0.023 and 0.013, respectively). Immunohistochemistry also revealed a lower number of LDCs in COPD patients than in non-COPD subjects. Conclusions Cigarette smoke, rather than airflow limitation, is the main determinant of impaired DCs maturation in the lung.

Patient-reported outcomes and considerations in the management of COPD: focus on aclidinium.

Chronic obstructive pulmonary disease (COPD) is a complex heterogeneous disease, in which several factors combine to give the final clinical expression. Both early and more recent studies have shown that forced expiratory volume in one second (FEV1), despite being an extremely important parameter to predict the progression of the disease, is a poor surrogate marker for symptoms perception. Accordingly, patient-reported outcomes (PROs) have gained popularity as a measure of the impact of treatment from the patients’ perspective, since they represent the individuals’ perception of their health status, beyond any physiological limitations. Several such PROs, therefore, are currently included in multidimensional COPD evaluation. This multidimensional approach helps identify different patient types and individualize, up to a certain point, pharmacological treatment. In this multidimensional approach it is important to highlight the importance of long-acting bronchodilators in COPD treatment strategies. Long-acting bronchodilators are cost-effective and have been shown to achieve the greatest functional and clinical improvements in COPD. As a result, long-acting bronchodilators are now the main pharmacological treatment for COPD at all stages of the disease. Until recently, tiotropium was the leading bronchodilator for the treatment of COPD. The clinical development of this medication, unprecedented in inhaled therapy, involved tens of thousands of patients and yielded consistent outcomes in terms of lung function, symptoms, quality of life, exacerbations, and prognosis. However, new long-acting bronchodilators have recently been developed or are currently under development. In this review, we evaluate the effects of aclidinium bromide, a novel long-acting bronchodilator, on PROs in COPD. Aclidinium is a novel long-acting muscarinic antagonist with a good safety profile for the treatment of COPD, and has proven efficacy in both objective functional measurements and PROs. Comparison studies with tiotropium have shown it to have similar lung function improvement and a similar impact on PROs, including quality of life or symptom perception.

Implications of the inflammatory response for the identification of biomarkers of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by both local and systemic inflammation. Because inflammation plays a critical role in the development, course and severity of COPD, inflammatory markers have the potential to improve the current diagnostic and prognostic approaches. Local inflammation in COPD is characterized by an infiltration of inflammatory cells, with an increased expression of cytokines, chemokines, enzymes, growth factors and adhesion molecules. Systemic low-grade inflammation is another common but nonspecific finding in COPD. Exacerbations of COPD are acute clinical events accompanied by an exaggerated inflammatory response. Future investigations in the field of COPD biomarkers should take into account different study designs and biochemical assays, disease course and duration, variations in symptom severity and timing of measurement.

Agudizaciones de la enfermedad pulmonar obstructiva crónica y condensación radiológica: tres preguntas controvertidas

Exacerbations of chronic obstructive pulmonary disease (COPD) are important because they have an impact on morbidity, mortality and healthcare costs. So far the diagnosis and treatment of exacerbations remains relatively homogeneous rules that apply equally to all exacerbations are based on bronchodilators, systemic corticosteroids and antibiotics as pillars of treatment.1 However, as with the expression of the disease in the stable phase, exacerbations have a rich and different clinical expression with different subtypes being identified with prognostic implications.2 In this context, the presence of pulmonary consolidation in a patient with an exacerbation of COPD is a subject of ongoing controversy. According to previous guides,3 the community-acquired pneumonia was included among the causes of exacerbation in the past. However, currently, it is considered an infectious comorbidity, clearly distinct from an exacerbation.1 In this regard, several questions can be identified. If we consider that the 2 processes are completely different, then does the exacerbation of COPD have distinguishing features compared to community-acquired pneumonia? In the present issue of Archivos de Bronconeumología, Boixeda et al.4 analysed a group of 124 patients with COPD requiring hospital admission for lower respiratory tract infection, comparing those with pulmonary condensation versus those without. With the cautiousness derived from an observational study with some imbalance between groups and the limitations of a bivariate analysis, the authors find differences between the 2 conditions in various clinical and laboratory parameters. Interestingly, the yield of sputum culture is similar in both process and the outcome too. The acute phase reactants such as C-reactive protein, the serum alpha1 band in the proteinogram or fibrinogen are highly increased in